Table 3 displays some of the more commonly encountered causes of neutrophilia in the clinical setting. Contrary to often popular belief, non-malignant leukocytosis, like fever, is typically not a detriment to the host. An exception to this general dictum is that patients with an entity known as the hypereosinophilic syndrome, a disease characterized by chronic eosinophilic leukocytosis, may suffer tissue damage from toxic products released by eosinophils.
The heart is especially susceptible to eosinophilic-induced toxicity which can be fatal. Neutrophilic leukocytosis most often is reactive in nature in response to an infection or inflammatory process. However, the one situation in which extreme leukocytosis e. Briefly, this syndrome occurs mainly in patients with de novo AML or as a complication of a blast crisis which inevitably occurs in patients with chronic myelogenous leukemia.
In these conditions, immature, malignant leukemic cells pathologically adhere to the microvasculature endothelium in the brain and lungs leading to microvascular occlusion and ischemic stress resulting in cerebral infarction and respiratory compromise. The leukemic cells release cytokines and toxins, further leading to local tissue damage. Unless urgently treated with leukopheresis, the leukostasis syndrome is fatal.
Leukopenia is a less commonly encountered problem in routine practice than is leukocytosis. Nonetheless, a busy clinician will encounter this problem not infrequently, especially in the hospital setting or the intensive care unit. For a more detailed discussion, the reader is referred to hematology texts or specialty review articles. Rather, the goal of this section is to provide a simple, yet thoughtful, approach to leukopenia. In general, leukopenia may result from decreased marrow production of leukocytic precursors, by peripheral destruction or sequestration of circulating leukocytes, or by autoimmune celluar damage or destruction.
The most common etiology of leucopenia is decreased marrow production due to a variety of disorders that damage the developing leukocyte mass in the bone marrow. For instance, cytotoxic chemotherapy damages leukocyte precursors leading to poor production and leukopenia, especially neutropenia.
Many other drugs can cause marrow suppression of which include antibiotics, cardiac drugs, and anti-rheumatic drugs. Sepsis and overwhelming infection can cause bone marrow suppression and leukopenia, which is a poor prognostic sign in the setting of sepsis.
Infiltration of the bone marrow by leukemia or myeloma cells as well as cancer cells can suppress normal cell production leading to various cytopenias. A clue to bone marrow infiltration with cancer, granulomas, or fibrotic tissue is the presence of circulating erythocyte and leukocyte precursors on the peripheral blood smear, a phenomenon known as a leukoerythroblastic blood picture. As such, it behooves the clinical to review the blood smear if leukopenia is prolonged or unexplained.
Leukopenia may also result from the peripheral destruction of cells within the reticuloendothelial system or spleen, a typical scenario occurring in patients with portal hypertension and cirrhosis or splenomegaly associated with myelo-lymphoproliferative disorders.
Patients with advanced cirrhotic liver disease can develop leukopenia, anemia, and thrombocytopenia from increased stasis, stagnation, and destruction of blood elements within the engorged spleen. Autoimmune leukopenia can occur with rheumatic diseases such as systemic lupus erythematosus from autoantibodies destroying leukocytes, most commonly the neutrophil.
Felty's syndrome is an autoimmune complication of rheumatoid arthritis that consists of neutropenia and splenomegaly. Autoimmune drug reactions can cause leukopenia on occasion by directing antibodies at epitopes on developing or circulating leukocytes.
Selected etiologies of neutropenia are noted in Table 4. The clinician should approach leukopenia by one of the mechanisms noted in the above section. Examples of specific types of neutropenia are noted above as examples but many other etiologies exist.
One should be aware that on average, black patients have lower neutrophil counts than whites. Appreciating this epidemiologic fact may prevent needless evaluation of a low-normal leukocyte count in an otherwise healthy black patient with normal peripheral blood smear cyto-morphology.
Often, the cause of neutropenia is obvious as in the setting of recently administered cytoxic chemotherapy, portal hypertension, leukemia, disseminated cancer, or autoimmune disease.
However, occult deficiencies of vitamin B12 or folate may inhibit nuclear maturation of not only erythrocytes but also of leukocytes and may lead to leukopenia, anemia, and thrombocytopenia. Aplastic anemia due to drugs e.
Myelodysplastic syndromes often cause leukopenia, but discussion of these disorders is beyond the scope of this text. Congenital causes of neutropenia are uncommon and are often associated with other systemic symptoms, and are also beyond the scope of this chapter. The most feared complication of leukopenia is suppression of the neutrophil cell line and subsequent neutropenia.
Patients with this degree of neutropenia typically have received cytotoxic chemotherapy, but a variety of other disease states can cause severe agranulocytosis.
Patients with severe neutropenia may present with fatigue, fever, malaise, and oral ulcerations, which can be exquisitely painful. A primary site of infection may be evident if cough, dysuria, or skin lesions are present. However, the lack of circulating neutrophils may limit the degree of inflammatory reaction at the infection site leading to a paucity of localizing symptoms. Furthermore, diagnosis of bacterial infection may be limited in patients with severe neutropenia since the lack of inflammation may impede detection of pulmonary infiltrates in patients with pneumonia, pyuria in the case of a urinary tract infection, or a discrete abscess in cases of intraabdominal or soft tissue infection.
Clinical suspicion of leukopenia may be heralded by oral ulceration and fever. Leukocytosis may be suspected in a patient with a fever or localizing signs or symptoms of infection.
In the patient with acute leukemia or aplastic anemia, symptoms and signs of anemia or thrombocytopenia may predominate. For instance, anemia may be associated with dyspnea, fatigue, and pallor. Furthermore, thrombocytopenia may cause mucosal bleeding or petechiae. Definitive diagnosis of quantitative leukocyte disorders, however, hinges upon obtaining a total leukocyte and differential count, which typically is ordered as a component of the complete blood count, or CBC.
In the case of leukopenia, the total leukocyte count will be decreased; the differential count then reveals which cell line is affected. Other cells lines such as lymphopenia, monocytopenia, eosinopenia, and basopenia are not uncommon, but will not be discussed further. An elevated total leukocyte count is usually due to an increase in circulating mature and immature neutrophils.
The differential count will reveal this or abnormalities in other cell lines. In routine clinical practice, neutrophilia is the most common cause of absolute leukocytosis. However, in patients with leukemoid reactions, persistent leukocytosis, or unexpected leukocytosis, the clinician may need to consider sinister conditions such as malignancy or a primary bone marrow disorder such as leukemia or a myeloproliferative disease.
In these cases, a manual differential count and blood smear should be obtained for a hematologist, oncologist, or pathologist to review. Often, the diagnosis of leukemia or an infiltrative bone marrow disease may be made if blast cells or a leukoerythroblastic blood picture are present, respectively.
At times it may be difficult to delineate between a benign leukemoid reaction and leukemia, especially chronic myelogenous leukemia CML. In this circumstance, the clinician may order a leukocyte alkaline phosphatase LAP score to aid in diagnosis. A low score classically is associated with CML and a high LAP score typically occurs with benign or reactive neutrophilia. Exceptions to these general rules do apply, and the interested reader is referred to subspecialty textbooks.
In addition, the lung is often the first organ to undergo dysfunction during sepsis due to its early involvement in the inflammatory process.
Hypotension is a serious sign in sepsis. In general, hypotension can be caused by a decrease in blood volume, a decrease in vascular tone, or a decrease in cardiac output. The hypotension of sepsis can be caused by reductions in all three parameters.
Initially, sepsis usually reduces blood volume by increasing capillary leakage, so the administration of fluids is an early priority during treatment Munford, In sepsis, the blood volume is not only reduced but it is redistributed ineffectively.
Fluid resuscitation will usually refill the under-perfused arteries. The spread of inflammatory mediators to the lung damages the vascular endothelium, and the alveolar capillaries become leaky. This leads to edema, poor lung compliance, and decreased oxygenation of the blood. Thus, septic patients often have tachypnea, labored breathing, crackles on auscultation, hypoxemia, and hypercapnia. If ARDS develops, a chest x-ray usually shows diffuse bilateral pulmonary infiltrates.
In a septic patient who does not have a history of major heart problems, cardiac output the volume of blood pumped by the left ventricle per minute can remain fairly constant. With expanded ventricles, each contraction expels more blood than usual. The increased cardiac output persists even when septic shock sets in. Cardiac output is the volume of blood that the heart pumps per minute. The classic presentation of sepsis includes an increased cardiac output. In early sepsis, hypotension is typically due to loss of intravascular volume, not to decreased cardiac output.
When septic shock sets in, it is usually an extracardiac problem because the vasculature has lost the ability to maintain its tone by responsive arterial constriction. Much of the cardiovascular dysfunction caused by sepsis is reversible. Brain dysfunction in patients with severe sepsis is called septic encephalopathy. This condition manifests as a change in mental status, with disorientation, confusion, agitation, lethargy, or coma.
Focal or unilateral neurologic signs are uncommon in septic encephalopathy. Blood work for a suspected case of sepsis includes a complete blood count, a platelet count, and a DIC panel prothrombin time, activated partial thromboplastin time, and the serum concentrations of fibrinogen, D-dimer, antithrombin III, and lactate Jui, Blood cultures should be drawn before antibiotics are administered Dellinger et al.
Poor tissue perfusion is a hallmark problem in sepsis. To have an adequate oxygen carrying capacity, a patient needs a sufficient quantity of red blood cells. Complications, such as bleeding or hemolysis as occurs in clostridial infections , can cause acute drops in the hematocrit Shapiro et al.
Sepsis usually produces an elevated white blood cell count, with an increased number of neutrophils and an increased percentage of immature forms called bands ie, a left shift, or bandemia Munford, The absence of an elevation of the white blood cell count does not rule out sepsis. Some septic patients develop an abnormally low white blood cell count leukopenia. Leukopenia with a fever is a particularly worrisome combination and increases the risk of a fatal outcome Shapiro et al.
Approximately half of all patients with sepsis have low platelet counts thrombocytopenia. As the sepsis worsens, platelet counts will continue to drop. When a septic patient has a combination of coagulation abnormalities the risk of DIC is increased. Protein C is a natural anticoagulant factor that helps to counteract the coagulation cascade.
A low blood concentration of activated protein C is typical of sepsis, because the cytokines that are released in the inflammatory condition of sepsis make it more difficult for protein C to be activated. Decreased levels of activated protein C in the circulation are associated with thrombi, microthrombi, and fibrin deposition in septic patients Shapiro et al. Recent attention has focused on the topic of biomarkers measurable characteristics used as indicators of a disease state.
Serum lactate has been the most studied. Lactic acid is a product of cell metabolism and is produced by the breakdown of carbohydrates when oxygen levels are low. Whether it is caused by poor perfusion or an impaired clearance secondary to organ dysfunction, multiple studies have shown that elevation in serum lactate is an effective marker to measure the risk of severe sepsis.
Studies have demonstrated that elevations in serum lactate without hypotension were associated with increased mortality in patients who present to the ED with severe sepsis. Recent studies suggest that serum lactate may perform well as a screening test in the medical decision-making process regarding early ED management and disposition of the septic patient Perman et al.
As early as it was proposed that serum lactate measured during critical illness correlated with adverse outcomes. This finding was further validated in and is now suggested by the Surviving Sepsis Campaign as an inclusion criterion for the 3-hour and 6-hour bundles for septic patients.
This can help identify and treat severe sepsis patients earlier in their clinical course so as to halt the inflammatory cascade and reverse perfusion abnormalities. Lactate should be re-measured within the first 6 hours of treatment to assess for normalization of levels after oxygen, antibiotics, and fluid support are given Dellinger et al. We have seen that sepsis can be triggered by an infection of any type of microbe. Additionally, our data set only includes data on the day of arrival to ICU and after ICU admission, without the ability to evaluate laboratory values prior to ICU admission that may aid in prognostic evaluation.
Among critically ill patients with suspected infection, leukopenia was rare, but associated with increased risk of death as compared with leukocytosis. Although leukopenia did not independently add to prognostic validity of the SOFA score above platelet count, the correlation of leukopenia with thrombocytopenia and association of neutropenia with mortality suggest that future studies should whether leukopenia or neutropenia may prospectively identify a larger group of patients earlier than current Sepsis-3 definitions.
We would like to acknowledge the work of researchers at the MIT Laboratory for Computational Physiology, collaborating research groups, patients and funders for making MIMIC a publicly available research resource. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Background Although both leukocytosis and leukopenia have been considered Systemic Inflammatory Response Syndrome criteria, leukopenia is not generally considered a normal response to infection.
Methods We performed a retrospective cohort study using the Medical Information Mart v1. Results We identified 5, ICU patients with suspected infection; 4. Conclusions Among ICU patients with suspected infection, leukopenia was associated with increased risk of death compared with leukocytosis.
Funding: The authors received no specific funding for this work. Background Prior to , [ 1 ] consensus definitions conceptualized sepsis as suspected infection with evidence of systemic inflammatory response syndrome SIRS [ 2 ].
Download: PPT. Exposures, covariates, and outcomes of interest We determined exposures and covariates in the time window from 48 hours before to 24 hours after the onset of suspected infection. Sensitivity analysis We conducted a sensitivity analysis where we restricted our cohort to patients with an ICD-9 code for infection, to increase the likelihood that the cohort included patients with confirmed, rather than suspected, infection. Table 1. Fig 2. Exploratory analysis: Sequential analysis of individual organ dysfunction scores, leukopenia, and mortality The coagulation component of the SOFA score platelet count was most responsible for attenuating the association between leukopenia and mortality Table 3.
Fig 3. Correlation of platelet count with white blood cell count. Table 3. Beta-estimates before and after adjustment for specific organ dysfunction. Discussion In order to evaluate the potential role of leukopenia as a marker of life threating organ dysfunction within the conceptual model of Sepsis-3, we determined the association between leukopenia and mortality among patients admitted to the ICU with suspected infection.
Conclusions Among critically ill patients with suspected infection, leukopenia was rare, but associated with increased risk of death as compared with leukocytosis. Supporting information. S1 Table. Odds ratios for neutropenia models. S2 Table. Odds ratios for Lymphopenia models. Acknowledgments Declarations We would like to acknowledge the work of researchers at the MIT Laboratory for Computational Physiology, collaborating research groups, patients and funders for making MIMIC a publicly available research resource.
References 1. JAMA ;— Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest ;— Incidence and prognostic value of the systemic inflammatory response syndrome and organ dysfunctions in ward patients. Epidemiological features and prognosis of severe community-acquired pneumococcal pneumonia.
Intensive Care Med ;— Prognostic significance of the neutrophil count in immunocompetent patients with bacteraemia. Qjm ;—9. Evaluation of definitions for sepsis.
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