Clinical Features

Because fever is often the first and occasionally the only sign of infection in the neutropenic cancer patient, a careful history and physical examination must be performed; this includes an evaluation of the fundi (looking for Candida endophthalmitis), rectum, perineum and groin (for perirectal abscess), skin and mucous membranes (for any lesions suggesting malignant disease or cellulitis), axillae, and catheters. The oral cavity and the perianal area are inspected, although digital rectal examination is discouraged in that it may induce bacteremia. Common infections may be manifested atypically because of lack of neutrophils. In the absence of polymorphonuclear cells, traditional markers of inflammation such as erythema, warmth, and pyuria may be absent or minimal, making it essential to search for subtle signs of inflammation. For example, skin infections may be manifested as a subtle rash or erythema, meningitis may be present without nuchal rigidity, urinary tract infection may be asymptomatic and without pyuria, and a lung infection may be present without pulmonary infiltrates. Conversely, on occasion, a neutropenic patient may not present with fever despite infection; this occurs more commonly in elderly patients and patients receiving corticosteroids.

Many factors predispose the neutropenic patient to infection and sepsis: prolonged bed rest; clinical deterioration; nutritional compromise; disruption of mucous membranes and skin barriers; indwelling catheters; and central nervous system (CNS) dysfunction secondary to cancer, sedatives, opiates, and psychotropic medications. An undetected and untreated infection can be rapidly fatal in this population of patients. Therefore early administration of broad-spectrum empirical antibiotic therapy is recommended in all febrile, neutropenic patients. Consultation with the oncologist and infectious disease specialist will help categorize the risk for patients and aid in the selection of antibiotics based on local resistance patterns (Box 123-3).

Diagnostic Strategies

While antibiotics are being started, diagnostic testing includes a complete blood count with differential cell count, platelet count, prothrombin time, partial thromboplastin time, blood chemistries, urinalysis, and analysis of any accessible sites suggestive of infection. Two sets of blood culture specimens are recommended for aerobic, anaerobic, and fungal growth. If an indwelling catheter is present, at least one set of blood culture specimens should be obtained from the device lumen as well as from a peripheral vein. A routine chest radiograph is obtained at most institutions. However, studies show that a chest radiograph is not necessary in patients with no respiratory symptoms and normal physical examination findings.⁹ Urine should be sent for culture even in the absence of pyuria. However, the use of sputum culture and Gram’s stain has become controversial because of inconsistencies in collection and preparation that have led to false-negative and false-positive results.

Some oncologists discourage rectal temperature readings for patients with neutropenia because of the risk of tearing the rectal mucosa and establishing a potential nidus for disseminated infection. However, this has not yet become the standard of care and may vary among institutions. An indwelling nasogastric tube predisposes the neutropenic patient to sinusitis. When imaging for suggested sinusitis is required, computed tomography (CT) is preferred to sinus films. A lumbar puncture, preceded by head CT, is indicated when symptoms point to the CNS.¹⁰ Some authorities have recommended surveillance cultures of the stool, nose, and throat. This recommendation is not universally accepted and is generally not indicated in patients with solid tumors.

Despite an intensive and comprehensive evaluation, an infectious cause is initially substantiated in only 30% of febrile, neutropenic patients.¹¹

Differential Considerations

Overall, approximately 85% of the initial pathogens isolated in febrile neutropenic patients are bacterial, and of these, 60 to 70% are gram-positive pathogens. Gram-negative bacilli, particularly Pseudomonas aeruginosa, were the most common pathogens until the 1980s. However, the administration of prophylactic antibiotics primarily active against gram-negative pathogens during chemotherapy, the widespread use of indwelling venous catheters, and the newer chemotherapy regimens have led to an increase in gram-positive pathogens.¹²

Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus epidermidis are the predominant gram-positive organisms. Once believed to be a skin contaminant, S. epidermidis has arisen as a major pathogen and may be resistant to antistaphylococcal penicillins and cephalosporins. Escherichia coli, P. aeruginosa, and Klebsiella pneumoniae remain the most common gram-negative pathogens.

Fungal, viral, and parasitic infections are also important primary and secondary complications. Fungal infections, especially with Candida albicans, can be a major problem in neutropenic febrile patients treated with broad-spectrum antibiotics for protracted periods. Although significant institutional variation has been noted, Histoplasma, Cryptococcus, Aspergillus, and Phycomycetes are additional fungal pathogens encountered in the compromised host. In contrast to patients with acquired immunodeficiency syndrome (AIDS), parasitic infections are not a common source of infection in patients with solid tumors. Pneumocystis jiroveci (formerly carinii), however, may be seen when corticosteroid use or hematologic malignant disease has resulted in lymphocyte dysfunction. Herpes simplex, herpes varicella-zoster, and cytomegalovirus are common viral pathogens. The compromised host is at risk for infection from a large number of individual pathogenic agents, thus further complicating the diagnosis and treatment of these patients.

In an attempt to prevent these infections, oncologists may initiate antimicrobial prophylaxis with trimethoprim-sulfamethoxazole (Bactrim) or quinolones for immunosuppressed patients before development of fever.¹¹ In addition, recombinant human granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor are used to stimulate rapid increase in granulocytes in neutropenic patients in an effort to decrease the duration and degree of neutropenia and immunosuppression.

Fever is occasionally without a source and is believed to arise from the underlying disease, although it is impossible to differentiate by clinical and demographic factors those patients with bacteremia-induced fever from those with unexplained fever. In addition, the absence of physical findings indicative of infection does not exclude a potentially life-threatening septic event because at least 50% of septic patients lack any distinct physical findings.

Management

Local resistance patterns are used to guide treatment. Patients are risk stratified and then treated accordingly. Patients with fever who appear in good condition are considered at low risk. Patients with fever who have severe neutropenia, appear ill, and are expected to have a protracted course are at high risk.¹³ In the initial evaluation and management of the febrile cancer patient, one must take into account the particular underlying malignant neoplasm, prior use of antimicrobial therapy, and how the degree of treatment has affected the host’s immunologic compromise. For example, in acute leukemia, normal circulating neutrophils and monocytes are largely replaced by blast cells, which do not function well in the phagocytosis and killing of bacterial and fungal agents. Chemotherapeutic agents and irradiation exacerbate or potentiate the underlying defect in already compromised host defenses. Corticosteroids impair granulocyte and mononuclear cell mobilization in leukemic patients. Patients with severely compromised host defenses and those in whom fever is accompanied by an increase in respiratory rate, change in mental status, agitation or apprehensiveness, and hemodynamic instability should be urgently treated.

Once febrile neutropenia is diagnosed, broad-spectrum antibiotic therapy is indicated immediately after culture specimens are obtained regardless of evidence of infection. Afebrile patients with neutropenia and suspicion of infection should also be cultured and should be treated with broad-spectrum antibiotics.

The optimal antimicrobial regimen is synergistic, broad spectrum, and bactericidal with a low potential for toxicity and chosen for efficacy against the most likely causes of systemic and rapidly progressing infection: S. aureus, S. epidermidis, E. coli, P. aeruginosa, and Klebsiella species. Traditionally, a two-drug regimen was selected because historical studies from the 1980s found that patients with gram-negative bacteremia had a higher survival rate when the isolate was sensitive to and treated with two antibiotics, compared with when the isolate was sensitive to only one of two antibiotics in the combined regimen.

Significant advances in the antimicrobial armamentarium have been made in the past 10 years with the development of broad-spectrum single agents such as the carbapenems (imipenem-cilastatin, meropenem) and the third- and fourth-generation cephalosporins (ceftazidime, cefepime). These agents, when investigated as monotherapy in neutropenic, febrile patients, have been found to be as effective as a dual-drug combination of an antipseudomonal penicillin (ticarcillin, carbenicillin, or piperacillin) plus an aminoglycoside (gentamicin or tobramycin). Furthermore, single-drug therapy is associated with fewer adverse effects.⁸ Amikacin is generally reserved as a second-line aminoglycoside for isolates that demonstrate aminoglycoside resistance. Antifungal and antiviral agents are not usually indicated during initial therapy, although they are becoming increasingly prevalent. Antifungal therapy is recommended if there is no improvement within 3 days of treatment.⁸ Box 123-3 summarizes current recommendations for antimicrobial therapy for fever in neutropenic cancer patients.

The drug most commonly used for treatment of gram-positive bacteria is vancomycin.⁸ Use of empirical vancomycin is indicated in the following circumstances:

Neutropenic febrile patients are best admitted to an isolation room, and rapid movement out of a congested waiting room into a private space is a high priority. Handwashing and reverse isolation techniques should be used.

Several clinical trials validate the outpatient management of selected patients older than 16 years with neutropenic fever. These patients must be at low risk for serious infection and must have close follow-up and unrestricted access to health care professionals.¹⁴ The Multinational Association for Supportive Care in Cancer has introduced a prediction tool to assess patients suitable for outpatient therapy that accounts for burden of illness and social factors.¹⁴

Contraindications to outpatient therapy are as follows:

The best-studied outpatient antibiotic regimen for neutropenic fever is a combination of ciprofloxacin (500 mg every 8 hours) and amoxicillin-clavulanate (Augmentin; 500 mg every 8 hours). Daily assessment by a health care professional is recommended for the first 3 days to ensure compliance and tolerability. All decisions involving disposition should be made in concert with the patient’s primary care physician, oncologist, or both.

Colony-stimulating factors are used in prophylaxis of neutropenic fever. However, their routine use as an adjunct to antibiotics in the treatment of neutropenic fever is controversial and currently recommended only in select, high-risk patients.¹⁵ Initiation of treatment should be made in consultation with the patient’s oncologist.

Epidemiology

Superior vena cava syndrome (SVCS) is an acute or subacute process caused by the obstruction of blood flow through the superior vena cava (SVC) secondary to compression, infiltration, or thrombosis. It occurs in approximately 1500 persons in the United States annually.¹⁶ Malignant disease is the most common cause of SVCS and currently accounts for 60 to 85% of cases.¹⁷ It is estimated that 2 to 4% of all cancer patients will have SVCS; in fact, SVCS is often the initial presenting sign of the tumor, and it is a poor prognostic marker.¹⁸

The most common cancers associated with SVCS are non–small cell lung cancer (50%), small cell lung cancer (25%), and lymphoma and metastatic lesions (10%).¹⁷ However, benign causes of SVCS, such as intrinsic thrombus, are gradually increasing, accounting for 20 to 40% of all cases owing to more frequent use of intravascular devices.¹⁹ Other common nonmalignant causes are goiter, pericardial constriction, primary thrombosis, idiopathic sclerosing aortitis, tuberculous mediastinitis, fibrosing mediastinitis (histoplasmosis and methysergide treatment), arteriosclerotic or (rarely) luetic aneurysm, nephritic syndrome, and indwelling central venous catheters. In contrast to SVCS in the adult population, SVCS in pediatric patients is most often iatrogenic secondary to indwelling catheters, ventriculoperitoneal shunts, and complications of cardiovascular surgical procedures.

Clinical Features

Knowledge of the unique anatomic relationship of the SVC in the anterior superior mediastinum is crucial to understanding of the clinical presentation of SVC obstruction. The SVC is easily compressed by any of its contiguous structures (trachea, heart, aorta, azygos vein, and paratracheal and bronchial lymph nodes). This compression can produce a constellation of symptoms that reveal the likely site of the pathophysiologic process (Fig. 123-1). The SVC arises from the innominate veins, which in turn arise from the internal jugular and subclavian veins. The azygos vein, the last main auxiliary vessel of the SVC, drains blood from the chest wall. As a consequence of this anatomic relationship, if the SVC is blocked above or at the entrance of the azygos, blood may bypass and decompress the obstruction through the chest wall collateral vessels and rejoin the SVC through the azygos. If the obstruction falls below or at the entrance of the azygos, blood must traverse in a retrograde manner down the azygos and other chest wall veins to reach the drainage area of the inferior vena cava and subsequently cause more prominent symptoms.

When the SVC is obstructed, blood flows through a collateral vascular network, but it generally takes weeks for these vessels to sufficiently dilate to accommodate the blood flow of the SVC. The severity of SVCS varies with the rate and degree of obstruction. When the obstruction occurs more slowly and the SVC is less compressed, there is more time for development of collateralization, which results in less severe symptoms.

Because the clinical features of the SVC are characterized by venous hypertension within the area ordinarily drained by the SVC, many of the findings are more noticeably evident in the recumbent or stooped-over position.

SVCS symptoms develop during a period of 2 weeks in about one third of patients and in a longer time in others.¹⁶ SVCS causes edema of the upper body, particularly of the head and neck. Early signs may include periorbital edema, conjunctival suffusion, and facial swelling, which will be most evident in the early morning hours and subside by midmorning. This edema may be significant enough to compromise the lumen of the trachea, causing stridor and dyspnea, or of the esophagus, causing dysphagia. One of the most common presentations in SVCS is dyspnea and swelling of the face, trunk, and upper extremities. Cough, dysphagia, and chest pain are less commonly reported, each occurring in approximately 20% of patients. With increasing impedance to blood flow, the full-blown syndrome begins to be manifested with thoracic and neck vein distention (67% and 59%, respectively), facial edema (56%), tachypnea (40%), tightness of the shirt collar (the Stokes sign), plethora of the face, edema of the upper extremities, and cyanosis.¹⁶ Other concerning symptoms are neurologic, such as headaches, confusion, and even coma, suggesting cerebral edema, ischemia, or both. Although cerebral edema is rare, it can be fatal. The usual course of SVCS is that collaterals develop, and symptoms improve when this occurs.¹⁷

There is little evidence in the literature to substantiate the notion of untreated SVC obstruction as immediately life-threatening, as was once believed, except when it occurs with respiratory compromise or cerebral edema.²⁰ Survival in patients with SVCS depends mainly on the course of the underlying disease.

SVCS can occur in conjunction with spinal cord compression (Rubin’s syndrome). Venous obstruction usually develops before the spinal cord compression, which is localized in most instances to the lower cervical or upper thoracic spinal cord. This syndrome is most commonly found with malignant neoplasms of lymphoma and lung cancer. Patients with venous obstruction and back pain or peripheral neurologic concerns should be evaluated with magnetic resonance imaging (MRI) of the vertebral spinal cord.

Ancillary Evaluation

The clinical diagnosis of SVC obstruction is mimicked by a few other clinical entities, most noteworthy of which are pericardial tamponade and heart failure; both can usually be excluded by physical examination and bedside cardiac ultrasound examination. The chest film is abnormal in 84% of patients with SVCS; the most common abnormalities are mediastinal widening (64%) and pleural effusion (26%).¹⁶ It reveals a mass in nearly 10% of patients. When superior mediastinal mass is present, 75% are on the right side, and in approximately 50% of patients, the masses are combined with pulmonary lesions or hilar adenopathy. Pleural effusion is an associated finding in approximately 20 to 25% of patients and is customarily found in the right hemithorax.

CT of the chest with intravenous administration of contrast material is the most useful imaging study to evaluate the SVC.¹⁶ History and physical examination combined with the CT chest scan with intravenous contrast enhancement will help differentiate between intrinsic and extrinsic compression of the SVC. The presence of collateral vessels with compression of the SVC is a reliable indicator of SVCS. Venography is relatively contraindicated because of its concomitant bleeding complications. It is generally warranted only during placement of a stent or surgery. MRI may be useful in patients who cannot receive an intravenous contrast agent. Invasive diagnostic procedures, including bronchoscopy, mediastinoscopy, scalene node biopsy, and limited thoracotomy, are commonly used to establish the diagnosis and extent of the disease.

Morbidity secondary to excessive bleeding from puncture sites has been reported rarely with venous access procedures for SVC. Intravenous injections may be less reliable because of slowing of drug distribution. Low flow rates may result in local irritation with thrombosis or phlebitis. Venous access is preferable on the side contralateral to the obstruction.

Once SVC obstruction is suggested, the appropriate consulting services should be contacted and plans for prompt diagnosis undertaken.

Management

SVCS is considered an immediately life-threatening oncologic emergency only if CNS symptoms are present. If a true emergency exists, a stent can be emergently placed in the SVC or radiation therapy can be used.²¹ In all other cases, once the clinical diagnosis is entertained, a tissue biopsy specimen should be obtained promptly before treatment decisions are made. Although supportive therapy may be instituted to alleviate symptoms, definitive therapy is dependent on the histologic diagnosis. The American College of Chest Physicians and the National Comprehensive Cancer Network both recommend consideration of radiation therapy, stent placement, or both. Historically, emergent radiation therapy was the treatment of SVCS. Currently, this is recommended only emergently for patients who present with stridor due to central airway obstruction or severe laryngeal edema. In an attempt to relieve the obstruction, current management uses radiation therapy for cancers responsive to this treatment and chemotherapy in other cancers because of the increased incidence of tumor sensitivity to newer antineoplastic agents. Complete relief of symptoms is achieved with chemotherapy in approximately 80% of patients with non-Hodgkin’s lymphoma or small cell lung cancer and in 40% of those with non–small cell lung cancer.¹⁶ However, temporizing measures that alleviate symptoms related to vascular compression should be rapidly instituted.

All management begins with attention to airway. Although no data exist to document its effectiveness, elevation of the head of the bed will theoretically decrease the hydrostatic pressure and thereby the edema with minimal risk. Glucocorticoid therapy (dexamethasone, 4 mg every 6 hours) is not well studied, but case reports do suggest benefit as a temporary measure. Loop diuretics have been used with transient symptomatic relief; they must be used judiciously to avoid hypovolemia, which may result in decreased blood flow.

Other current management approaches include percutaneous transluminal stent placement and bypass surgery.²¹ Placement of an intravascular stent to bypass the obstruction is particularly useful in patients requiring urgent intervention before tissue diagnosis because of severe symptoms such as respiratory distress. Stent placement is also useful for patients whose cancer is minimally responsive to chemotherapy or radiation therapy and for those patients with a thrombus associated with an indwelling catheter. Surgical bypass grafting is infrequently used to treat SVCS but may be useful in cancers resistant to chemotherapy and radiation therapy.

The prognosis for patients treated for SVCS depends on the tumor type, with better survival rates in patients with lymphoma than in patients with bronchogenic carcinoma. Median life expectancy of patients with malignant causes of SVCS is 6 months, but this varies widely by the underlying malignant condition.²⁰