Differential Diagnosis

The Process of Differential Diagnosis

May 24, 2017 Uncategorized No comments , , , , ,

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Elements of the Differential Diagnosis

Decision-making on the Basis of Diagnosis. The physician endeavors to organize the subjective complaints and the objective findings of a patient in order to receive further indications to proceed. This approach is frequently chosen because a diagnosis in the conventional sense is not always easy to make, as more than one diagnosis can often be possible at the same time. Therefore, an important first step is to create a list of problems with a detail description.

Dynamics of Reaching a Diagnosis. The diagnosis is of utmost importance not only for the prognosis but also for the introduction of an appropriate therapy. An established diagnosis always needs to be reassessed. Secondary diseases, complications, and side-effects can supervene. Each diagnosis continues to be a differential diagnosis, since the particular symptoms, even during the course of a disease, have to be continually reevaluated, carefully considered, and differentiated. For a proper evaluation of the symptoms and risk factors, knowledge of their clinical meaning is crucial. Consequently, the purpose of differential diagnosis is to point out what disease can occur, when specific symptoms appear, and what risk factors with the utmost probability accompany specific diseases. In most cases, there are numerous possibilities and additional factors that have to be taken into account. Exclusively listing all the possibilities would not be beneficial.

Practical Procedure for Establishing a Diagnosis

The diagnosis is based on four essential aspects:

  • medical history
  • state of health
  • laboratory and other investigations
  • monitoring

In case of an unsolved disease, the number of possible remaining diagnoses can be reduced drastically via history-taking and clinical examination. The additional morphological, physical, chemical, and biological examinations allow the isolation of the most probable diagnosis. Monitoring is a critical quality control of the previous diagnostic process, as well as the subsequent therapeutic decisions.

Cardinal Symptoms. In differential diagnosis we proceed from a single dominant symptom, or group of symptoms or main symptoms, and try to classify as much as possible on the basis of the current research, in order to obtain a clinical picture. In most cases, a differential diagnosis is considered when a cardinal symptom indicates the direction of further measures. This leading symptom can emerge from the medical history, from clinical findings, as well as from laboratory work results. So-called problem-oriented patient care is practiced in a similar manner.

Correct Evaluation of Evident Findings and the Differential Diagnosis

Process of Clinical Judgement. The correct evaluation of findings is crucial for the diagnosis. Positive and negative predictive values play important roles in this context. Nevertheless, personal intuition with regard to the individual patient remains an important factor.

Pathognomonic symptoms or combinations of symptoms are rare, but must be recognized when present. Except in the most obvious cases, we are subject to continuous uncertainty in everyday clinical life – we must use the available resources to decide on the most probable diagnosis for our individual patients and select the most effective treatment. It is assumed that with additional clinical experience the correct clinical judgement will automatically be made. In this we are supported by studies that critically analyze individual investigative steps and diagnostic processes. Guidelines which critically assess current research and place it in context are often helpful.

Probability-based Decision Analysis. In cases of ambiguous and usually complex situations, the physician can decrease the probability of error when diagnosing or excluding a disease using reasoning based on decision analysis. He or she analyses the probability of a disease diagnosis on the basis of the findings (post-test probability), whereby both the sensitivity and specificity of the test must be given, as well as considering the pretest probability (current probability).

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Diagnostic Process. The path from unspecified disease to definitive diagnosis is only rarely a linear one by which data are first collected and then analyzed according to established criteria. Additional examinations are to be conducted as indicated, whereupon everything is reevaluated in order to make a definite diagnosis. Frequently, only a few minutes into a medical discussion, first working hypotheses are formulated that ultimately direct further history-taking and examination.

Preliminary Diagnosis and Immediate Therapeutic Consequences. The first impression is on the one hand crucial, but on the other hand can be dangerous if not continually challenged by results of ongoing examinations. It is essential to recognize serious disease as early as possible, and to quickly initiate the appropriate measures, which are often vital to the prognosis. During the diagnostic process it is therefore often necessary to introduce therapeutic measures without a firm diagnosis, and independent of the specific etiology. Treatment on the basis of a preliminary diagnosis is often acceptable for most common diseases.

In cases of new symptoms or an “atypical” course of disease, the diagnosis should be challenged. The following possibilities must be considered:

  • The first diagnosis was wrong
  • The diagnosis was correct, a complication supervened
  • The diagnosis was correct, a secondary independent disease supervened
  • The diagnosis was correct, side effects from therapy occurred
  • The diagnosis was correct and the course of the disease is indeed atypical

Factors that Can Influence the Differential Diagnostic Thought Process

Prevalence of Disease

Differential diagnosis is based on the knowledge as to which symptoms and disease are common. According to an American study involving over 300 million cases of consultations in private practices of internists, the most common complaints are: abdominal pain, thoracic pain, back pain, headaches, fatigue, coughing and catarrhal symptoms, as well as leg pain, skin symptoms, and vertigo.

Differential diagnosis also takes into account the frequency of diseases according to the overall situation.


The influence of age must always be considered. Knowledge of age distribution provides valuable clues for the diagnosis.


Some diseases occur more frequently in males than in females, and vice versa. This is especially true for occupational diseases as well as diseases caused by smoking or alcohol. Because on their anatomic configuration, women are susceptible to reoccurring urinary tract infections, pyelonephritis and iron deficiency due to menorrhea.


Lifestyle is very important to people today. Some positive habits are healthy nutrition and fitness; harmful habits include addictive behaviors. The influence of alcohol especially on the liver, blood pressure, and nervous system is well known. Smoking, which is particularly on the rise in adolescents, is responsible for the emergence of vascular diseases as well as pulmonary diseases.

Eating Habits

Eating habits are at least partly responsible for many diseases. To a large extent, obesity is closely associated with disease. Diabetes mellitus type 2, arthrosis, and hypertension are more frequently observed in obese persons. Obesity is one of the risk factors in the development of arteriosclerosis and its consequences. Also the influence of eating habits with regard to malignant tumors is suggested.

Season, Time of Day, and Weather

Certain diseases are clearly dependent on the season:

  • Food-associated infectious diseases in particular, e.g., salmonellosis, occur more frequently in warm seasons.
  • The seasonal emergence of allergic coryza depends on airborne pollens (spring/summer)
  • Respiratory infections occur more frequently during the winter months and cause higher morbidity and mortality in the elderly population, especially in a humid climate and after sudden changes of weather (influenza, respiratory syncytial virus).

Circadian rhythms also plays a role. Chronic polyarthritis is a disease with an explicit circadian rhythm and reaches maximum activity in the early morning and a minimum of activity in the afternoon. Accordingly, a correlation with the circadian cortisone output and neutrophil count has been identified.

Geographic Distribution

The geographic distribution of diseases must often be considered. It is especially obvious in infectious diseases (tropical diseases), where climatic and hygienic conditions exert influence. The physician is obliged to consider “exotic” diseases in the differential diagnosis of patients with a history of travel (tourism). In addition, even similar clinical pictures (e.g., malaria) result in a different disease course depending on the country of infection (differences in resistance).

Ethnic Groups

The patient’s ethnic background can be of importance for the diagnosis. Thalassemia occurs primarily in populations bordering the Mediterranean. Sickle cell anemia is present nearly exclusively in black populations.

Profession and Leisure

The profession of a patient can provide diagnostic clues. Occupational diseases are defined by a clear correlation between occupational activity and disease.

Besides occupational diseases, leisure pursuits are to be considered. Diseases are often observed due to sporting activities.

Precluding or Promoting Diseases

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From medical experience, certain diseases rarely occur simultaneously, whereas others are associated with each other. Patients with chronic alcohol abuse seldom develop liver cirrhosis and chronic pancreatitis at the same time. Similarly, there are practically no incidences of malaria in patients with sickle cell anemia. Diseases of one organ can be the initial manifestation of an overall dysfunctional organism or a systemic disease that endangers practically all organs. Thus upon emergence of symptoms, other possible manifestations and locations should be carefully considered.

Differential Diagnosis by Groups of Diseases

When differentiating a clinical picture, very often it is initially impossible to identify the real diagnosis, namely the nosological entity. Until relevant findings are present, one has to be content with the classification into one of the groups of diseases. In all unclear cases, consideration is almost always given to this at the beginning of the differential diagnostic process.

  • Degenerative conditions
  • Infectious disease
  • Immune mediated diseases
  • Tumors
  • Metabolic diseases
  • Dysfunction of the endocrine system
  • Mental disorders
  • Hereditary diseases
  • Allergies
  • Intoxications

Clinical Skills – Cluster the Clinical Findings

April 18, 2017 Clinical Skills, Differential Diagnosis, History Taking No comments

It is often challenging to decide whether clinical data fit into one problem or several problems. If there is relatively long list of symptoms and signs, and an equally long list of potential explanations, one approach is to tease out separate clusters of observations and analyze one cluster at a time. Several clinical characteristics may help.

Patient age: The patient’s age may help; younger adults are more likely to have a single disease, whereas older adults tend to have multiple diseases.

Timing of symptoms: The timing of symptoms is often useful. For example, an episode of pharyngitis 6 weeks ago is probably unrelated to the fever, chills, pleuritic chest pain, and cough that prompted an office visit today. To use timing effectively, you need to know the natural history of various diseases and conditions.

Involvement of different body systems: Involvement of the different body systems may help group clinical data. If symptoms and signs occur in a single system, one disease may explain them. Problems in different, apparently unrelated, systems often require more than one explanation. Again, knowledge of disease patterns is necessary.

Multisystem conditions: With experience, you will become increasingly adept at recognizing multi system conditions and building plausible explanations that link manifestations that are seemingly unrelated. To explain cough, hemoptysis, and weight loss in a 60-year-old plumber who has smoked cigarettes for 40 years, you would rank lung cancer high in your differential diagnosis. You might support your diagnosis with your observation of the patient’s cyanotic nailbeds. With experience and continued reading, you will recognize that his other symptoms and signs fall under the same diagnosis. Dysphagia would reflect extension of the cancer to the esophagus, pupillary asymmetry would suggest pressure on the cervical sympathetic chain, and jaundice could result from metastases to the liver. Related risk factors should be explored promptly.

Key questions: You can also ask a series of key questions that may steer your thinking in one direction and allow you to temporarily ignore the others. For example, you may ask what produces and relieves the patient’s chest pain. If the answer is exercise and rest, you can focus on the cardiovascular and musculoskeletal systems and set the gastrointestinal (GI) system aside. If the pain is more epigastric, burning, and occurs only after meals, you can logically focus on the GI tract. A series of discriminating questions helps you analyze the clinical data and reach logical explanations.

Evidence-Based Medicine – How to Ask A Question

August 11, 2015 Clinical Trials, Evidence-Based Medicine, Pharmacy Informatics No comments , , , , ,

Foreground questions can be categorized into 5 types, including:

1.Therapy: determining the effect of interventions on patient-important outcomes (symptoms, function, morbidity, mortality, and costs)

2.Harm: ascertaining the effects of potentially harmful agents (including therapies from the first type of question) on patient-important outcomes

3.Differential diagnosis: in patients with a particular clinical presentation, establishing the frequency of the underlying disorders

4.Diagnosis: establishing the power of a test to differentiate between those with and without a target condition or disease

5.Prognosis: estimating a patient’s future course

Clinical questions often spring to mind in a form that makes finding answers in the medical literature a challenge. Dissecting the question into its component parts to facilitate finding the best evidence is a fundamental skill.

One can divide questions of therapy or harm into 4 parts following the PICO framework: patients or population, intervention(s) or exposure(s), comparator, and outcome. For questions of prognosis, you can use 1 of 2 alternative structures. One has only 3 elements: patients, exposure (time), and outcome. An alternative focuses on patient-related factors, such as age and sex, that can modify prognosis: patients, exposure (e.g., older age or male), comparison (e.g., younger age or female), and outcome. For diagnostic tests, the structure we suggest is patients, exposure (test), and outcome (criterion standard).

You need to correctly identify the category of study because, to answer your question, you must find an appropriately designed study. If you look for a randomized trial to inform the properties of a diagnostic test, you will not find the answer you seek.

Different structures or design of studies can investigate different foreground questions. To answer the foreground question that of interest, one should know these different structure or design of clinical studies. Because different study designs can correspond different type of foreground questions, I arrange following discussion due to the type of foreground questions.

Therapy and Harm

To answer questions about a therapeutic issue, we seek studies in which a process analogous to flipping a coin determines participant’s receipt of an experimental treatment or a control or standard treatment: a randomized trial. Once investigator allocate participant to treatment or control groups, they follow them forward in time to determine whether they have, for instance, a stroke or myocardial infarction – what we call the outcome of interest.

When randomized trials are not available, we look to observational studies in which – rather than randomization – clinician or patient preference, or happenstance, determines whether patients receive an intervention or alternative.

Ideally, we would also look to randomized trials to address issues of harm. For most potentially harmful exposures, however, randomly allocating patients is neither practical nor ethical. For instance, one cannot suggest to potential study participants that an investigator will decide by the flip of a coin whether or not they smoke during the next 20 years. For exposures such as smoking, the best one can do is identify observational studies (often sub classified as cohort or case-control studies) that provide less trustworthy evidence than randomized trials.

Differential Diagnosis

For sorting out differential diagnosis, we need a different study design. Here, investigators collect a group of patients with a similar presentation (e.g., painless jaundice, syncope, or headache), conduct an extensive battery of tests, and, if necessary, follow patients forward in time. Ultimately, for each patient the investigators hope to establish the underlying cause of the symptoms and signs with which the patient presented.


Establishing the performance of a diagnostic test (i.e., the test’s properties or operating characteristics) requires a slightly different design. In diagnostic test studies, investigators identify a group of patients among whom they suspect a disease or condition of interest exists (such as tuberculosis, lung cancer, or iron-deficiency anemia), which we call the target condition. These patients undergo the new diagnostic test and a reference standard (also referred to as gold standard or criterion standard). Investigators evaluate the diagnostic test by comparing its classification of patients with that of the reference standard.


A final type of study examines a patient’s prognosis and may identify factors that modify that prognosis. Here, investigators identify patients who belong to a particular group (such as pregnant women, patients undergoing surgery, or patients with cancer) with or without factors that my modify their prognosis (such as age or comorbidity). The exposure here is time, and investigators follow up patients to determine whether they experience the target outcome, such as an adverse obstetric or neonatal event at the end of a pregnancy, a myocardial infarction after surgery, or survival in cancer.