Infections in the outpatient cancer care
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1Summary
Infections are a common complication in patients with hematologic and oncologic diseases, also in the outpatient setting. They lead to distressing morbidity and can delay or compromise the delivery of effective antineoplastic therapy. Identification of risk factors for complicated infections reduces morbidity and mortality. Prevention of bacterial and viral infections through drug prophylaxis and consistent vaccination are key elements of this strategy. Precise clinical evaluation of patients with febrile neutropenia enables outpatient oral empiric therapy in many cases and avoids unnecessary hospitalization.
These recommendations are based on guidelines prepared by the German Infectious Diseases Working Party (AGIHO) for the prophylaxis, diagnosis and therapy of these patients and are available as short versions in Onkopedia. They are based on systematic literature searches, a uniform assessment of the strength of evidence (Table 1), and a consensus-building process.
2Basics
2.1Definition and basic information
Systemic therapy of hematologic and oncologic diseases can be performed in most cases on an outpatient basis. Even fragile, comorbid and elderly patients with tumor diseases are increasingly treated this way.
Patients with hematologic and oncologic diseases are per se immunosuppressed, even if no specific therapy has been administered. The risk of opportunistic infections increases with the type and intensity of specific therapy and correlates with the underlying disease, remission status and general condition of the patient. The spectrum of infectious complications is very heterogeneous and largely depends on the cellular immune status and the duration and depth of neutropenia. Infectious complications play an important role in morbidity and mortality in this population and are a major cause of therapy-associated deaths.
A large number of guidelines and recommendations for the management of opportunistic infections are available. These are usually written for specific patient populations (e.g., stem cell transplantation), for specific microbiologically confirmed infections or for a defined measure (prophylaxis or therapy). The aim of this review is to provide algorithms for prophylaxis, diagnosis and therapy of opportunistic infections in the outpatient setting. The recommendations are based on the current guidelines of the AGIHO. The algorithms apply to different constellations:
"watch and wait" situation
specific tumor therapy
follow-up after treatment
Symptom-oriented care without specific tumor therapy
The recommendations refer to adult patients.
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6Therapy and prophylaxis
6.1Prophylaxis
6.1.1Antibacterial prophylaxis
The indication for antibacterial prophylaxis is risk-adapted [1]. Besides the expected duration of neutropenia (see Table 2), additional clinical factors play an important role in assessing the risk of complicated infections, see Table 3.
2 Assessment of the indication for G-CSF administration and estimation of the risk under this aspect
The recommendations for the use of antibacterial prophylaxis are derived from this risk assessment. These are shown in Table 4 in relation to the clinical situation and the desired treatment goal.
Clinical situation | Intention | Intervention | SoR1 | QoE1 |
|---|---|---|---|---|
High risk and 1st cycle | Avoiding fever and infection | Antibacterial prophylaxis | A | I |
High risk and all other cycles | B | I | ||
Standard risk and 1st cycle | B | I | ||
Standard risk and all other cycles | C | I | ||
High risk | Mortality reduction | B | II | |
Standard risk | C | II | ||
Therapy with eculizumab, ravulizumab or splenectomy/with functional asplenia without effective meningococcal vaccination | Prevention of meningococcal infection | Penicillin V 250 mg b.i.d. or ciprofloxacin 1 x 500 mg/day until 4 weeks after vaccination or documentation of protective titers | A | IIu |
Both fluoroquinolones and cotrimoxazole can be used for antibacterial prophylaxis, see Table 5 and Table 6.
2 FQ = Fluoroquinolone
An algorithm for the use of antibacterial prophylaxis is shown in Figure 1. Antibacterial prophylaxis can successfully reduce febrile episodes and bacterial infections in neutropenic patients, although overall survival has not been shown to improve. The indication for antibiotic prophylaxis should be critically considered because of the associated side effects and with respect to increasing resistance. Furthermore, due to the continuous influence of antibiotic application on the composition of the intestinal microbiota as well as the selection of resistant bacterial strains, it is unclear whether the positive effect of prophylaxis is maintained during serial therapy cycles. Therefore, the evidence on the efficacy of antibacterial prophylaxis was analyzed and evaluated separately between the first cycle of therapy and subsequent cycles. If, from a clinical point of view, an indication for antibiotic prophylaxis can be made solely on the basis of the reduction of fever and infection after careful consideration of the adverse effects (development of resistance, toxicity, side effects), there is a high level of evidence for its effectiveness (A I) for the first cycle of therapy. The evidence for this strategy in patients at standard risk is significantly less strong (B I). The same applies to all subsequent therapy cycles for both risk groups: in view of the development of resistance and the lack of evidence, the effectiveness of prophylaxis for the prevention of fever and infections cannot be assessed with certainty here (high-risk B I - low-risk C I).
Heart failure
Renal failure
Leukocytopenia at start of therapy
Alkaline phosphatase and bilirubin elevated
Type and stage of underlying disease
Type and dose of chemotherapy
6.1.2Pneumocystis jirovecii prophylaxis
Pneumocystis jirovecii pneumonia is a serious complication in the treatment of hematology patients. The risk for the occurrence of this infection increases with the extent of cellular immunosuppression. A risk stratification is shown in Table 7.
Depending on the clinical risk, drug prophylaxis can be performed [1]. A selection of possible drugs in relation to the clinical question is shown with the corresponding recommendation grade in Table 8 and Table 9.
2 Trimethoprim-Sulfamethoxazole (Cotrimoxazole)
2Pneumocystis jirovecii pneumonia;
3 Desensitization may be considered in cases of known intolerance to cotrimoxazole (Pyle RC et., J Allergy Clin Immunol Pract, 2014, 2(1):52 - 8. [2]
The algorithm in Figure 2 outlines the prophylaxis of PjP infection according to the risk assessment.
2 see technical information in package insert
6.1.3Antifungal prophylaxis
Invasive fungal infections are very rare outside the treatment of acute leukemias or in the context of allogeneic stem cell transplantation. The reason for this is the short duration of neutropenia, which is usually less than seven days in the treatment of solid tumor patients. These patients are therefore at standard risk of neutropenic infectious complications.
There is no general indication for antifungal prophylaxis in this patient population. Local antifungal prophylaxis of oropharyngeal or esophageal Candida infections may be indicated for long-term use (≥ 4 weeks) of glucocorticoids or during radiation or radiochemotherapy of head and neck or esophageal carcinomas.
6.1.4Antiviral prophylaxis
6.1.4.1General
Viral infections are usually reactivations of pre-existing infections, such as hepatitis B or shingles. Primary viral infections occur primarily with respiratory or enteric viruses. The risk of reactivation correlates with the depth of cellular immunosuppression. Other risk factors include advanced age, prolonged neutropenia, advanced and uncontrolled underlying disease, and prolonged treatment with steroids. For antiviral prophylaxis in patients with hematologic/oncologic diseases outside of allogeneic stem cell transplantation, the following key principles apply in appropriate risk constellations [3]:
the administration of aciclovir or valaciclovir for the prophylaxis of herpes zoster
antiviral treatment to prevent reactivation of hepatitis B
vaccination against influenza (see Onkopedia guideline Vaccinations in tumor patients).
vaccination against SARS-CoV-2 (see Onkopedia guideline COVID-19 in patients with blood diseases and cancer)
The algorithm for antiviral drug prophylaxis is shown in Figure 3. Depending on clinical risk factors, drug prophylaxis with aciclovir or valaciclovir may be useful in specific clinical situations (AGIHO: moderate recommendation) [4].
2 Observe boosters according to Onkopedia guideline "Vaccinations in tumor patients“
3 Obligatory for prophylaxis of herpes zoster
6.1.4.2Hepatitis B
Patients with hematologic diseases, especially those receiving CD20 antibodies, anthracyclines, or high-dose steroids, should be screened for previous hepatitis B infection. Depending on the serostatus, the procedure for prophylaxis is selected [3]. Recommendations for screening and prophylaxis are shown in Figure 4.
6.1.4.3Vaccinations
Prevention of infectious complications is an important element in the reduction of morbidity and mortality from tumor therapy. In addition to avoidance of exposure and to drug prophylaxis, vaccination is an effective measure in prevention. The vaccination strategy depends on the extent of immunosuppression as a consequence of the underlying disease, the specific tumor therapy and the current vaccination status of the patients [5].
In principle, vaccinations with live vaccines should be avoided in immunocompromised patients. Vaccination with inactivated vaccines is usually safe. An overview of the recommendations for vaccination of hematological-oncological patients against specific pathogens is given in Table 9.
Patients receiving anti-CD20 therapy must be considered separately. The resulting B-cell depletion persists for at least 6 months after completion of treatment. However, B-cell function is necessary to establish an adequate vaccination response, therefore vaccination can only be useful after recovery of the humoral immune response. Vaccination strategy should follow these two main principles:
Vaccination of patients against SARS-CoV-2 is definitely recommended.
All vaccinations should be carried out according to individual benefit assessment. Household contacts of tumor patients should also be motivated to update their own vaccination protection. The protective effect of herd immunity for tumor patients is of primary importance if patients themselves cannot be vaccinated.
The evidence basis of the implementation of vaccination varies. Recommendations are summarized in Table 10.
2 vaccination with live MMRV (measles, mumps, rubella, varicella) vaccines should not be performed (D-IIt); recommendation BIIt refers to vaccination after definitive cytoreductive treatment OR use of a dead vaccine, if applicable.
6.1.5Febrile neutropenia
Fever in neutropenia is a major risk factor for morbidity and mortality after cytoreductive therapy and necessitates the immediate initiation of empiric antibiotic therapy. Fever in neutropenia is a hematologic emergency [6].
A microbiologically confirmed infection is practically never present at the time of fever onset. A thorough clinical examination to search for a source of infection is indispensable in order to be able to administer a calculated ("preemptive") antimicrobial therapy against a typical spectrum of pathogens, if appropriate. If no suspicious findings are found here either, the diagnosis is fever of unknown origin (FUO). This is treated empirically [6].
6.1.5.1Diagnostics
Recommendations for diagnostics in patients with febrile neutropenia are summarized in Table 11.
6.1.5.2Risk stratification
The main risk factor for the occurrence of febrile neutropenia and the associated complications is the duration of neutropenia [6]. Therapy-related neutropenia in outpatient tumor patients usually does not last longer than 7 days. These patients are therefore at standard risk for the occurrence of febrile neutropenia. Other risk factors include age, performance status, type and remission status of the underlying disease, extent of prior therapy, and comorbidity (impaired function of vital organ systems). Patients who are expected to have neutropenia for longer than seven days are considered to be at high risk for complicated febrile neutropenia. This is usually the case in patients with acute leukemias undergoing induction and consolidation therapies and allogeneic stem cell transplantation. The procedure for febrile neutropenia in this population requires inpatient care and is therefore not the subject of this guideline. We refer to the current AGIHO guideline on empirical antimicrobial therapy [6] and to the specific recommendations for suspected sepsis [7].
Patients who are expected to have neutropenia for ≤ 7 days may also be managed as outpatients with oral empiric antibiotic therapy under certain conditions. Numerous clinical parameters associated with a low risk of febrile complications help to assess the likely course of febrile neutropenia, see Table 12.
The Multinational Association of Supportive Care in Cancer (MASCC) has established a risk score based on individual factors [8], see Table 13.
Validation of the score showed that patients with a score above 20 (73% of the total group) could be assigned to a low/standard risk cohort. The rate of complications was 6%, and the rate of death was 1%. 39% of patients with a score of <21 (27% of the total group) had complicated FN and a case fatality rate of 14%. Thus, these patients are at high risk for an unfavorable outcome of FN.
6.1.5.3Therapy of febrile neutropenia at standard risk based on the MASCC score
The MASCC score thus identifies patients at low risk for complicated FN using simple clinical parameters. Therefore, outpatient care can be targeted. However, further factors describing the social environment and compliance must be examined. These factors play an important role in the safe outpatient care of febrile patients. To evaluate use using a further risk checklist, see Table 14.
Parameter |
Medical care is ensured |
Patients are not alone and can be reached by phone |
Clinic with hematologic-oncologic competence reachable in 1 hour |
Oral medication can be safely administered with high compliance |
Patients are fully conscious and understand the clinical situation |
No prophylaxis with fluoroquinolones performed |
Hemodynamic stability |
No signs of organ failure |
Consistent interrogation and assessment of risk leads to an algorithm for identifying patients with febrile neutropenia who can be referred to outpatient therapy, see Figure 5.
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9References
Classen AY, Henze L, von Lilienfeld-Toal M et al. Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematologic malignancies and solid tumors: 2020 updated guidelines of the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO/DGHO). Ann Hematol 2021;100:1603-1620. DOI:10.1007/s00277-021-04452-9
Pyle RC, Butterfield JH, Volcheck GW et al Successful outpatient graded administration of trimethoprim-sulfamethoxazole in patients without HIV and with a history of sulfonamide adverse drug reaction. J Allergy Clin Immunol Pract 2014;2:52-58. DOI:10.1016/j.jaip.2013.11.002
Sandherr M, Hentrich M, von Lilienfeld-Toal M et al. Antiviral prophylaxis in patients with solid tumours and haematological malignancies-update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). Ann Hematol 2015; 94:1441-1450. DOI:10.1007/s00277-015-2447-3.
Henze L, Buhl C, Sandherr M et al. Management of herpesvirus reactivations in patients with solid tumours and hematologic malignancies: update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and medical Oncology (DGHO) on herpes simplex virus type 1, herpes simplex type 2, and varicella zoster virus. Ann Hematol. 2022;101:491-511. DOI:10.1007/s00277-021-04746-y
Rieger CT, Liss B, Mellinghoff S et al. Anti-infective vaccination strategies in patients with hematologic malignancies or solid tumors-Guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). Ann Oncol 2018; 29:1354-1365. DOI:10.1093/annonc/mdy117
Heinz WJ, Buchheidt D, Christopeit M et al. Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO). Ann Hematol 2017; 96:1775-1792. DOI:10.1007/s00277-017-3098-3.
Kochanek M, Schalk E, von Bergwelt-Baildon M et al. Management of sepsis in neutropenic patients: 2018 guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO). Ann Hematol 2019; 98:1051-1069. DOI:10.1007/s00277-019-03622-0.
Klastersky J, Paesmans M, Rubenstein EB et al. The Multinational Association for Supportive Care in Cancer risk index. J Clin Oncol 2000; 18:3038-3051. DOI:10.1200/JCO.2000.18.16.3038.
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16Disclosure of Potential Conflicts of Interest
| Author | Employer1 | Consulting / Expert opinion2 | Shares / Funds3 | Patent / Copyright / License 4 | Fees5 | Funding of scientific research6 | Other financial relations7 | Personal relationship with authorized representatives8 |
|---|---|---|---|---|---|---|---|---|
| Maschmeyer, Georg |
Klinikum Ernst von Bergmann gGmbH Potsdam
|
No
|
No
|
No
|
Yes
Vorträge und/oder Moderation von Symposien:
Merck-Serono, Gilead Sciences, AstraZeneca, GlaxoSmithKline, Forum für Medizinische Fortbildung, RG Medizinische Fortbildung, MedUpdate, Uniklinik Kiel, Uniklinik Leipzig, Landesapothekerkammer Baden-Württemberg, OSHO Services
|
No
|
No
|
No
|
| Rieger, Christina | Conflict of interest declarations pending | |||||||
| Sandherr, Michael |
MVZ Penzberg, Starnberger Kliniken GmbH
|
Yes
Roche, BMS, Lilly
|
No
|
No
|
Yes
Roche, BMS, Lilly
|
No
|
No
|
No
|
2 - Activity as a consultant or expert or paid participation in a scientific advisory board of a company in the health care industry (e.g., pharmaceutical industry, medical device industry), a commercially oriented contract research organization, or an insurance company.
3 - Ownership of business shares, stocks, funds with participation of companies of the health care industry.
4 - Relates to drugs and medical devices.
5 - Honoraria for lecturing and training activities or paid authors or co-authorships on behalf of a company in the health care industry, a commercially oriented contracting institute or an insurance company.
6 - Financial support (third-party funds) for research projects or direct financing of employees of the institution by a company in the health care industry, a commercially oriented contract institute or an insurance company.
7 - Other financial relationships, e.g., gifts, travel reimbursements, or other payments in excess of 100 euros outside of research projects, if paid by an entity that has an investment in, license to, or other commercial interest in the subject matter of the investigation.
8 - Personal relationship with an authorized representative(s) of a healthcare company.
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