General Approach to Infectious Diseases Evaluation

Infections are disorders or diseases caused by microorganisms such as bacteria, viruses, fungi, or parasites. Infections manifest themselves by a myriad of signs and symptoms in a variety of combinations. It is not possible to discuss in a meaningful way the various permutations and combinations of signs and symptoms associated with infectious diseases. However, some signs and symptoms are, rightly or wrongly, widely regarded as cardinal manifestations of infection and are discussed here.


Fever is defined as an elevation of normal body temperature. Definitions of normal temperature have evolved over the years through studies that have attempted to incorporate potential confounding factors such as time of day, age, gender, and body site of temperature measurement in their evaluations. Based on data from these studies, fever is defined as an oral temperature of ≥37.2°C (99.0°F) in the morning or an oral temperature of ≥37.8°C (100°F) at any time during the day.

Fever is a component of a complex physiologic reaction often, but not exclusively, in response to invasion by microorganisms or their products. Body temperature is regulated by a complex process that involves a variety of body structures, including the immune system, heat and cold receptors in the skin and organs, and the spinal cord and the brain. Thus fever may be caused by a variety of other noninfectious conditions ( Table 1.1 ). Alternatively, fever may not be present though the patient clearly has an infection (e.g., typhoid fever, tularemia, brucellosis, and dengue).

Take-Home Points Box 1.1

Take-Home Points:

  • 1.

    Infections commonly present with fever.

  • 2.

    Infections can present without fever.

  • 3.

    There are many noninfectious causes of fever.


Noninfectious Causes of Fever

Disease Conditions Examples
Malignancies Lymphoproliferative disorders
Renal cell cancer
Hepatocellular cancer
Autoimmune/connective tissue diseases Vasculitis
Temporal arteritis
Systemic lupus erythematosus
Still disease
Thromboembolic disease Deep venous thrombosis
Pulmonary emboli
Acute stroke
Drugs Antibiotics
Contrast dye
Others Inflammatory bowel disease
Rheumatic fever


The stem cells in the bone marrow that form the various blood cells—hematopoietic stem cells—produce erythroblasts, megakaryoblasts, lymphoblasts, and myeloblasts. Erythroblasts further differentiate into red blood cells, megakaryoblasts into platelets, and lymphoblasts into lymphocytes. Myeloblasts differentiate into monocytes and granulocytes, and granulocytes are further categorized into neutrophils, basophils, and eosinophils. The term white blood cell (WBC) denotes the cells derived from lymphoblasts and myeloblasts. Upon maturation, most (80% to 90%) of the WBCs remain in the bone marrow, a few (2% to 3%) circulate freely in the peripheral blood, and the remainder are stored in the spleen or deposited along the walls of the blood vessels.

Leukocytosis—an increase in the total number of WBCs due to any cause—is a reaction to a wide range of events that result in the release of various cytokines, which in turn mediate the release of leukocytes and their precursors from the marrow, spleen, and vessel walls. A rise in the absolute number of neutrophils is most commonly responsible for the overall leukocytosis, but increases in the numbers of the other components of WBCs—lymphocytes, monocytes, eosinophils, or basophils—may also play a role.

Infections are common causes of leukocytosis. However, leukocytosis can also be the result of a variety of other stimuli and conditions, including malignancies, inflammatory conditions, drugs, stress, and trauma ( Table 1.2 ).


Noninfectious Causes of Leukocytosis

Disease Conditions Examples
Malignancies Lymphoproliferative disorders
Renal cell cancer
Autoimmune/connective tissue diseases Vasculitis
Rheumatoid arthritis
Systemic lupus erythematosus
Physiologic Strenuous exercise
Emotional disorders
Drugs Corticosteroids
Others Inflammatory bowel disease
Rheumatic fever
Acute hemorrhage

Occasionally, the magnitude of leukocytosis exceeds 50,000 cells/mm 3 , requiring distinguishing it from leukemia. This is called a leukemoid reaction and is commonly caused by severe infections.

At times, leukopenia (a decrease in total WBCs) and not leukocytosis may be the presenting feature of certain infections. These infections include influenza, infectious mononucleosis, HIV, rickettsiosis, ehrlichiosis, typhoid fever, tuberculosis (TB), brucellosis, tularemia, leishmaniasis, and malaria. Sepsis, or any overwhelming infection, can also present with leukopenia.

Take-Home Points Box 1.2

Take-Home Points:

  • 1.

    Infections commonly present with leukocytosis.

  • 2.

    Infections can also present with leukopenia.

  • 3.

    There are many noninfectious causes of leukocytosis.

Inflammatory Markers

Inflammatory markers are certain proteins that are released into the bloodstream as part of the body’s response to an inflammatory insult or injury such as infections and systemic rheumatologic/autoimmune disorders. The inflammatory markers most commonly used in clinical practice are C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The ESR measures the rate of fall of red blood cells to the bottom of a test tube in 1 hour. When blood contains higher amounts of certain inflammatory proteins such as fibrinogen and immunoglobulins, the red blood cells fall more rapidly. Thus the rate of erythrocyte sedimentation is increased. Any condition, including noninflammatory conditions such as age, anemia, obesity, and pregnancy, can cause increases in ESR. CRP is produced by the liver in response to inflammatory cytokines, with the rate of production proportional to the magnitude of the inflammation. In general, clinicians use CRP and ESR to identify a generalized inflammatory state—including infections—to monitor disease activity, or to monitor response to treatment. Infections that have been classically associated with elevations of CRP and/or ESR include cellulitis, necrotizing skin and soft tissue infections, osteoarticular infections, endocarditis, and TB. The utility of these inflammatory markers in infections is as a nonspecific tool for identifying these conditions and to monitor their response to therapy as an adjunct to overall clinical assessment and other, more specific diagnostic tests.

Take-Home Points Box 1.3

Take-Home Points:

  • 1.

    Inflammatory markers can aid in identifying certain infections.

  • 2.

    Inflammatory markers can aid in monitoring response of certain infections to treatment.

  • 3.

    Inflammatory markers are nonspecific and are elevated as a result of a variety of inflammatory and noninflammatory conditions.

  • 4.

    When used in diagnosing and/or managing infections, inflammatory markers play a subordinate role to overall clinical assessment and other, more specific diagnostic tests.

Mimickers of Infection

A variety of local or systemic conditions, including malignancies, autoimmune diseases, inflammatory conditions, and drug effects, may mimic an infectious process ( Table 1.3 ). Familiarity with these conditions is important for appropriate diagnosis and management and avoidance of unnecessary antimicrobial treatment.

Syndrome Infectious Etiology Noninfectious Mimic
Cellulitis Beta-hemolytic streptococci, most commonly group A ( Streptococcus pyogenes in children and non–group A streptococci in adults)
Staphylococcus aureus
Less common:
Haemophilus influenzae, Clostridium species
Streptococcus pneumoniae
Related to specific exposures:
Pasteurella multocida
Aeromonas hydrophila
Vibrio vulnificus
Pseudomonas aeruginosa, Erysipelothrix rhusiopathiae
Venous stasis
Contact dermatitis
Relapsing polychondritis
Eosinophilic cellulitis
Diabetic myonecrosis
Recurrent UTI Chronic bacterial prostatitis, perinephric abscess, infected renal stone, urinary tract obstruction, genitourinary structural abnormalities Interstitial cystitis
Kidney stone
Loin pain hematuria syndrome
Nonresolving pneumonia Mycobacterial, fungal, bronchiectasis Malignancy, interstitial lung disease, hypersensitivity pneumonitis
Chronic meningitis Mycobacterium tuberculosis
Bacterial ( Brucella , Nocardia , Tropheryma whipplei , Leptospira , Borrelia burgdorferi, etc.)
Viral (HSV, HIV, CMV, HTLV, Enterovirus), fungal ( Cryptococcus , Blastomyces , Coccidioides , Histoplasma , Sporothrix, etc.)
Parasitic ( Toxoplasma , Acanthamoeba, Angiostrongylus, etc.)
Connective tissue disease, malignancy, paraneoplastic, medication induced, genetic
Acute meningitis Bacterial ( Streptococcus pneumoniae , Haemophilus influenzae , Neisseria meningitidis , Listeria monocytogenes )
Viral (HSV, VZV)
Medication induced, connective tissue disease
Infected ulcers Bacterial
Parasitic ( Leishmania )
Pyoderma gangrenosum
Necrosis lipoidica
Septic arthritis Staphylococcus aureus
Gram-negative bacilli
Crystal-induced arthropathy
Pigmented villous nodular synovitis
Multifocal osteomyelitis Hematogenous dissemination due to endovascular infection SAPHO
Infective endocarditis Staphylococcus aureus,
Viridans group streptococci , Enterococci , Coagulase-negative Staphylococci , Streptococcus bovis , Nutritionally variant streptococci, Abiotrophia and Granulicatella species, HACEK, Fungi
Anti-phospholipid antibody syndrome
Libman-Sacks endocarditis
Marantic endocarditis
Degenerative valve changes
Chronic diarrhea Parasitic ( Cryptosporidium, Cyclospora, Entamoeba histolytica, Giardia, Microsporidia, etc.)
Viral ( Norovirus , Rotavirus, etc.)
Bacterial (Clostridioides difficile)
Inflammatory bowel disease
Celiac disease
Cystic fibrosis
Pancreatic insufficiency
Irritable bowel syndrome
Medications (laxative, etc.)
Fever of unknown origin Mycobacterial infections
Infective endocarditis
Occult abscesses
Malignancy (leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, atrial myxomas)
Connective tissue disease

CMV, Cytomegalovirus; HACEK, Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species; HSV, Herpes simplex virus; HTLV-1, human T lymphotropic virus 1; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis; UTI, urinary tract infection; VZV, Varicella zoster virus.

May 30, 2021 | Posted by in PUBLIC HEALTH AND EPIDEMIOLOGY | Comments Off on General Approach to Infectious Diseases Evaluation

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