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
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:
- 1.
Infections commonly present with fever.
- 2.
Infections can present without fever.
- 3.
There are many 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 Sarcoidosis Still disease |
| Thromboembolic disease | Deep venous thrombosis Pulmonary emboli Acute stroke |
| Drugs | Antibiotics Antineoplastics Allopurinol Contrast dye Interferon |
| Others | Inflammatory bowel disease Gout Rheumatic fever |
Leukocytosis
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 ).
| Disease Conditions | Examples |
|---|---|
| Malignancies | Lymphoproliferative disorders Renal cell cancer Sarcoma |
| Autoimmune/connective tissue diseases | Vasculitis Rheumatoid arthritis Systemic lupus erythematosus |
| Physiologic | Strenuous exercise Emotional disorders Pregnancy |
| Drugs | Corticosteroids Epinephrine Endotoxin Lithium Ranitidine Serotonin Histamine Heparin Acetylcholine |
| 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:
- 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:
- 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 Mycobacterial Parasitic ( Leishmania ) Fungal | Pyoderma gangrenosum Necrosis lipoidica |
| Septic arthritis | Staphylococcus aureus Streptococci Gram-negative bacilli | Crystal-induced arthropathy Hemarthrosis 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 Malabsorption Hyperthyroidism Irritable bowel syndrome Medications (laxative, etc.) |
| Fever of unknown origin | Mycobacterial infections Osteomyelitis Infective endocarditis Occult abscesses | Malignancy (leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, atrial myxomas) Connective tissue disease Miscellaneous |
