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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