New chemotherapeutic and immuno-modulating biologic agents offer significant improvement in the treatment of cancers and many chronic inflammatory diseases. However, these agents are associated with increased risk of infection.
Fever in a neutropenic patient is a medical emergency as a significant proportion of patients have bacteremia that is almost always fatal if untreated.
It is usually defined as a single temperature of >38.3ºC (101.3ºF), or a sustained temperature >38ºC (100.4ºF) for more than one hour.
Neutropenia is usually defined as an absolute neutrophil count (ANC) <0.5 x 109 cells/L or <1 x 109 cells/L with a predicted nadir of <0.5 x 109 cells/L.
The risk of infection in the neutropenic patient is related to the virulence of the pathogen, the immunologic impairment of the host, and the disruption of skin and mucosal barriers.
The risk for specific types of infection is also enhanced based upon the nature of the underlying malignancy and its associated immune defects. Abnormal antibody production or clearing of immune complexes in multiple myeloma, chronic lymphocytic leukemia and splenectomized patients, results in an increased risk of bacterial infection and sepsis with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis). The T cell defects associated with Hodgkin’s disease result in an increased risk of infection with intracellular pathogens such as Listeria monocytogenes, Salmonella spp., Cryptococcus neoformans, and Mycobacterium tuberculosis.
A very wide variety of microorganisms are possible pathogens in this setting but an infectious source is identified in only approximately 30 % of episodes. Often the only evidence of infection is bacteremia, which can be documented in approximately 25 %. Approximately 80% of identified infections are believed to arise from patients’ own endogenous flora.
Gram-negative bacilli, particularly P. aeruginosa, were the most commonly identified pathogens in the early days of chemotherapy and the empiric use of antipseudomonal antimicrobial agents became, and continue to be, the mainstay of therapy. In more recent times Gram-positive organisms (Staphylococcus aureus, Staphylococcus epidermidis, and streptococci) have been more commonly isolated.
Fungal pathogens are common, but usually arise later as a secondary infection in patients with prolonged neutropenia and antibacterial antibiotic use. Candida albicans and other Candida spp. are common fungal causes of line-related infections and can cause disseminated candidiasis. Aspergillus spp. are well described and feared fungal pathogens in immunocompromised hosts. Manifestations vary from localized skin ulcers, sinusitis and invasive pneumonia to fulminant disseminated disease. Fortunately, infections with Aspergillus spp. are quite rare in Newfoundland.
Viral infections are also common in this patient population. Herpes simplex viruses, HSV-1 and HSV-2, are common causes of skin eruptions. HSV can also cause encephalitis, meningitis, myelitis, esophagitis, pneumonia, hepatitis, erythema multiforme, and ocular disease. Herpes zoster often presents in an atypical disseminated pattern involving multiple dermatomes or widespread skin dissemination in immunocompromised hosts.
Evaluation of the Patient
All febrile neutropenic patients should have a careful history, review of symptoms, and detailed physical examination. It is always important to remember that in the absence of neutrophils, signs of inflammation can be extremely subtle. All indwelling line sites should be carefully examined for subtle signs of infection. Review of symptoms and a physical examination should be repeated daily.
Laboratory evaluations should include complete blood cell count with differential, transaminases, bilirubin, amylase and electrolytes, a chest radiograph, and cultures of blood, urine, and sputum if producing. Neutropenic patients with pulmonary infiltrates frequently cannot produce sputum; a more invasive approach including bronchoscopy or open lung biopsy may need to be pursued in order to make a microbiologic diagnosis.
In interpreting laboratory results in neutropenic patients, it is important to recognize that the absence of neutrophils cannot be used to exclude the possibility of infection. Therefore, absence of a cerebrospinal fluid pleocytosis, pyuria, or PMNs on sputum Gram stain does not rule out infection. If localizing signs or symptoms are present, other tests should be considered such as imaging of the CNS, sinuses, chest, abdomen, or pelvis, skin biopsy for culture, direct fluorescent antibody (DFA) testing for HSV or VZV, stool for culture, Clostridium difficile toxin, or ova and parasites.
Antibiotics must be instituted without delay and always include coverage for P. aeruginosa. Proven regimens include monotherapy with ceftazidime (used routinely in St. John’s), imipenem, meropenem, or cefepime OR double coverage with beta-lactam(with anti-pseudomonal activity) and an aminoglycoside, or a beta-lactam and a fluoroquinolone.
The addition of vancomycin should be considered in patients who present with hypotension, mucositis, skin or catheter site infection, history of MRSA colonization, or recent quinolone prophylaxis. Withdrawal of empiric vancomycin should be considered after 72 hours if cultures remain negative.
Antifungal therapy (amphotericin B, caspofungin, or voriconazole) is routinely added at five to seven days of neutropenia in patients with persistent fever in whom reassessment does not yield a cause. Fluconazole is generally not recommended for empiric antifungal therapy, because of concerns about efficacy (ineffective against Aspergillus spp., Candida krusei and Candida glabrata).
If an infectious source of fever is identified, antibiotics should be continued for at least the standard duration. With no known source, the timing of the discontinuation of antibiotics usually depends upon the fever response and resolution of the neutropenia.
Colony stimulating factors (CSF) have been reported to decrease the duration of neutropenia, fever, and hospitalization. However, CSF has not been shown to decrease mortality, beneficial effects are quite modest and these agents should not be used routinely for patients with fever and neutropenia.
Agents that block the action of tumor necrosis factor alpha (TNF-α) and recombinant interleukin-1 (IL-1) have been shown to be effective treatment modalities in patients with rheumatoid arthritis. It is not surprising, given the immunosuppressive effects of TNF-α and IL-1 blockers, infections have emerged as common complications of these agents. Microorganisms responsible for the infectious complications associated with anti-cytokine therapy are generally intracellular pathogens or organisms that commonly exist in a chronic, latent state and are normally held in check by cell-mediated immunity.
Agents targeting TNF-α
TNF has a central role in the pathophysiologic response to inflammation and infection. TNF is produced by a variety of inflammatory cells, predominantly macrophages and lymphocytes. Initially, TNF augments the inflammatory process by encouraging cell recruitment to the injured area, helping to localize and destroy the inciting agent. Later, TNF acts to limit the damage by inducing apoptosis of infected cells and maintaining the formation of granulomas. These essential functions are blocked by anti-TNF agents, leaving the patient at risk of new infection or reactivation of latent disease.
Currently there are three anti-TNF agents – infliximab (Remicade™), etanercept (Enbrel™), and adalimumab (Humira™). Infliximab has the most reports of opportunistic infections associated with it, presumably because it is the most potent inhibitor of TNF-α. In contrast, etanercept binds TNF-α with significantly lower affinity. There is less experience with adalimumab but it is expected to be similar to infliximab.
TB is the most commonly reported opportunistic pathogen associated with anti-TNF-α therapy. Disease results from reactivation of latent mycobacteria that have been present often for many years. Disease is often severe with extra-pulmonary and even widely disseminated disease being common presentations. Patients being considered for anti-TNF-α therapy should be screened for latent TB by taking an appropriate history for TB exposure and by PPD skin testing. A new test for latent TB is now being used in this setting. Quantiferon Gold™ is an interferon release assay performed on a blood sample with the advantage of being able to distinguish Mantoux positivity as a result of BCG immunization from true latent infection. Latent TB infection should optimally be treated before anti-TNF-α therapy is started. Furthermore, patients should be advised to seek medical attention if they develop symptoms consistent with TB during treatment with this agent.
Other reported unusual infections
Listeria monocytogenes (listeriosis), Histoplasma capsulatum (histoplasmosis), Pneumocystis jerovici pneumonia, aspergillosis and Cryptococcus neoformans.
Interleukin-1 receptor antagonist
Anakinra (Kineret™) is a recombinant human form of interleukin-1 receptor antagonist (IL-1RA) that binds to IL-1 receptors without activating the cell. This agent appears to be less likely than anti-TNF-α agents to induce opportunistic infection.
Steroids affect many aspects of the immune system. They inhibit superoxide production that results in a decrease in hydrogen peroxide generation and diminution in release lysosomal hydrolases within the phagocytic vacuole, thus interfering with the killing of microorganisms. Corticosteroids cause a weakening of collagen, and fibrous tissue support proteins in the skin and soft tissue leading to atrophy, easy bruising, and delayed wound healing. The resulting striae seen in individuals receiving chronic steroids makes the skin more susceptible to traumatic breaks, and infections caused by Staphylococcus aureus, Streptococcus pyogenes (Group A Streptococcus), and some gram-negative bacilli.
Infections associated with corticosteroids are dependent on the route of administration, dose, and duration of therapy. Inhaled steroids have the lowest risk of causing infection with the most common infectious complication being oropharyngeal candidiasis that is generally easily treated.
How much Corticosteroid makes someone clinically significantly immunosuppressed?
In general, the higher the dose and the longer the duration the more likely someone will suffer an opportunistic infection. Those that have received the equivalent of greater than or equal to 15 mg/day prednisone for at least 1 month are deemed “chronic steroid patients” and should receive special attention much like those receiving biologic agents as discussed above.
Like patients receiving anti-TNF-α therapy chronic steroid patients should receive isoniazid treatment if they have a positive Mantoux tuberculin skin test or Quantiferon Gold™ assay.
Chronic steroid patients are at increased risk of developing localized and disseminated infections with herpes zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, adenovirus, influenza and parainfluenza virus. They are also at increased risk of developing multi-dermatomal shingles, cutaneous dissemination and varicella zoster pneumonitis. Chronic steroid patients who have negative varicella titers should receive zoster immunoglobulin if exposed to chickenpox or shingles.
Chronic steroid use also increases the risk of infection with intracellular pathogens such as Listeria monocytogenes, Salmonella species, Brucella, and Legionella.
Corticosteroids are a major risk factor for disseminated Strongyloides stercoralis infection. It is important to screen patients from endemic areas for Strongyloides and treat this infection prior to initiating immunosuppressive therapy.
Always treat your patients with the smallest amount of immunosuppression possible and always have a heightened index of suspicion of infection in those unfortunate patients requiring significant immune modulating therapy.