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JuhaH.Salonen

Infections in Immunosuppressed and Cancer Patients

Essentials

  • Blood neutrophilic leucocyte count is immediately determined in a febrile immunocompromised patient.
  • The neutrophilic leucocyte count is more important than serum CRP for the decision on hospital admission.
  • Pneumococcal, meningococcal, Haemophilus influenzae and influenza vaccinations are recommended for splenectomized patients.

Diseases and drugs causing immunosuppression

  • Malignant haematological diseases
  • HIV infection
  • Congenital immunodeficiencies (hypogammaglobulinaemia, impaired phagocytosis, disorders of cell-mediated immunity)
  • Organ and stem cell transplantations
  • Prematurity (infants)
  • Cytotoxic drugs (including azathioprine and methotrexate prescribed for rheumatoid arthritis)
  • Cyclosporin, mycophenolate, tacrolimus
  • Glucocorticoids (daily doses equivalent to > 10 mg of prednisone)
  • Biological agents (inhibitors of TNF-alpha and other cytokines, rituximab, abatacept)
  • Antilymphocyte globuline

Causes of infection in patients with cancer

  • Neutropenia (after cytotoxic chemotherapy)
    • Gram-negative rod bacteria (enterobacteria, pseudomonas)
    • Staphylococcus aureus
    • Staphylococcus epidermidis (central venous catheter)
    • Viridans streptococci (mucositis)
    • Enterococci (perianal infections)
    • Yeasts (Candida species)
    • Aspergillus moulds (especially in severe and prolonged, i.e. lasting for several weeks, neutropenia)
  • Disorders of humoral immunity (myeloma, chronic lymphocytic leukaemia)
    • Bacteria with a capsule (pneumococci, Haemophilus influenzae, meningococcus)
  • Splenectomized patients
    • Pneumococci, Haemophilus influenzae, meningococcus
  • Disorders of cell-mediated immunity (HIV infection, lymphomas, organ transplantations, biological drugs)
    • Mycobacteria (tuberculosis reactivation, atypical mycobacteria)
    • Listeria
    • Salmonella
    • Herpes viruses (Herpes simplex, Varicella zoster, cytomegalovirus)
    • Toxoplasma
    • Pneumocystis jirovecii
    • Cryptococcus
    • Candida yeasts
    • Aspergillus moulds

Fever in the immunosuppressed patient Imipenem-Cilastatin for Febrile Neutropenic Patients, Empirical Anti-Gram-Positive Antibiotic Treatment for Febrile Neutropenic Cancer Patients, Granulocyte Transfusions for Treating Infections in Neutropenic Patients

  • In a febrile patient (fever > 38°C when measured twice with half an hour interval, or > 38.5°C in a single measurement), the blood granulocyte count is determined immediately.
    • If the neutrophilic leucocyte count exceeds 1 × 109 /l, the patient is generally treated as a normal patient with fever.
    • If the neutrophilic leucocyte count is below 1 × 109 /l a septic infection should be suspected and the patient should be admitted to a hospital.
    • In severely immunodeficient patients an empirical broad-spectrum antibiotic should always be started immediately after taking blood culture samples because the course of the disease is often violent and difficult to predict. The antibiotic therapy can later be changed after receiving answers from blood culture and sensitivity studies.
    • The empirical initial antibiotic agent for a neutropenic patient is either piperacillin-tazobactam or the combination of a third-generation cephalosporin and an aminoglycoside.
      • Aminoglycosides must not be used in patients with renal insufficiency or with risk factors that predispose the patient to renal insufficiency (e.g. nephrotoxic cytostatic drugs in use).
    • The minimum duration of antibiotic therapy for a neutropenic patient is 7 days, and the medication should not be discontinued until the patient has been afebrile for at least 4 days.
  • The absolute neutrophilic leucocyte count in the blood is more important than serum CRP for the decision on hospital admission.
  • Serum CRP concentration is usually high in a bacterial infection, but can be near normal right at the very beginning of the infection.
    • If the fever has lasted at least for 12 hours a normal serum CRP concentration almost rules out a serious bacterial infection.
  • High fever is the only certain sign of infection in a neutropenic patient, because the local inflammatory reaction and the imaging findings are often scarce during severe neutropenia.

Infections in cancer patients without severe neutropenia Oral Versus Intravenous Antibiotic Treatment for Febrile Neutropenia in Cancer Patients

  • The neutrophilic leucocyte count is above 1.0 × 109 /l.
  • The infections are often associated with obstruction, interruption of anatomical borders caused by tumours, invasive procedures, and tumour necroses.
  • The causative agents are ordinary virulent bacteria.
  • Long-lasting hospitalization exposes the patient to colonization caused especially by intestinal bacteria and therefore exposes the patient to severe infections.
  • The infections should be treated like infections in other immunosuppressed hospital patients.
  • Local radiation can increase the risk of infection by damaging the mucosal lining of the gastrointestinal tract.

Prevention of bacterial and fungal infections in neutropenic patients or patients who have received stem cell transplantation Granulocyte Transfusions for Preventing Infections in Patients with Neutropenia or Neutrophil Dysfunction

  • The key to preventing hospital-acquired infections is proper hospital hygiene in order to prevent the transmission of infections via hands. In addition, it is important to shorten the duration of neutropenia (leucocyte growth factors).
  • Even if prophylactic fluoroquinolones have been shown to reduce the occurrence of bacterial infections and febrile periods in neutropenic patients Antibiotic Prophylaxis for Neutropenic Patients, most experts are of the opinion that the harms caused by prophylactic use of antibacterial agents overweigh the potential benefits http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm.
  • Prophylactic use of antifungal agents has been shown to reduce superficial candida infections in the mouth and pharynx Preventing Oral Candidiasis in Cancer Patients.
  • The evidence on the prophylactic effect of antifungal medication in the prevention of deep infections is strongest in patients who have received allogeneic stem cell transplantation. According to the current view, routine fluconazole prophylaxis is indicated in these patients only.
    • The fluconazole dose in prophylactic use should be 400 mg/day.
    • Posaconazole has been shown to be more effective than fluconazole and itraconazole in the prevention of fungal infections in patients with acute myelogenous leukemia or myelodysplastic syndrome. However, as systematic use of antifungal prophylaxis in a large number of immunocompromised patients may lead to resistant fungal species to become more common, the use of prophylaxis should be assessed unit by unit and focus it to high-risk patients.

Prevention and treatment of infections in splenectomized patients

  • Splenectomy increases the risk of serious infections for the rest of the patient's life. The infections are associated with high mortality (as high as 60% in pneumococcal septicaemia).
  • The encapsulated bacteria pneumococci, Haemophilus influenzae type b and meningococci cause serious infections.
  • The risk of infection is also increased in patients with splenic insufficiency, including those with sickle cell anaemia, thalassaemia, essential thrombocytopenia, stem cell transplantation, and lymphoproliferative diseases.
  • The following vaccinations are recommended to patients who are splenectomized or who have impaired splenic function (see also possible national and local guidelines).
    • Pneumococcal vaccine for all patients
      • Pneumococcal conjugate vaccine (PCV13) is given 2 weeks before elective splenectomy. The vaccine covers 13 pneumococcal serotypes. The serotype coverage can be extended by giving the patient a 23-valent pneumococcal polysaccharide vaccine (PPV23) 8 weeks after the conjugate vaccine.
      • A booster of the PPV23 polysaccharide vaccine should be given at least once, 5 years after the first vaccination.
      • There is insufficient research evidence on the efficacy and safety of repeated booster doses.
    • Vaccine against Haemophilus influenzae type b
      • Recommended for patients who have not been vaccinated with Hib vaccine when they were children, or if the Hib series requires additional doses.
      • The vaccine is given only once.
    • Meningococcal vaccine
      • The vaccine does not protect from infections caused by type B meningococci. The protective effect against meningococci types A and C is rather short-lived. The meningococcal ACWY conjugate vaccine should be used. According to British guidelines meningococcal vaccination should be given to all patients after splenectomy, and before travelling to epidemic areas.
      • According to the current view, no boosters are required if the patient was given the conjugate vaccine.
    • Influenza vaccine
      • Vaccination against influenza should be performed annually because the vaccination decreases the risk of secondary bacterial infections.
  • The patients should carry a note about their splenectomy to inform health care personnel in emergencies.
  • In case of fever and chills or nausea the patient should contact a doctor immediately.
  • A course of amoxicillin-clavulanic acid is indicated after animal bites.
  • If a serious infection is suspected in a splenectomized patient a parenteral dose of penicillin can be administered before transportation to a hospital.
  • A blood sample for culture should be taken before giving penicillin if this can be carried out without delay.
  • People travelling to areas where malaria is endemic should be informed about the increased risk of severe malaria, and they should be provided with proper prophylaxis.

Varicella (chickenpox) and herpes zoster

  • The varicella virus causes a very severe and extensive disease in an immunodeficient patient who has not had varicella before.
    • A patient who has been exposed to varicella is given varicella zoster hyperimmune globulin within 3 days after the exposure.
    • If there are symptoms of varicella, antiviral medication (intravenous aciclovir) is started immediately because untreated primary varicella is associated with very high mortality among immunodeficient patients.
  • Also herpes zoster (the reactivation of varicella virus) may be unusually violent and widespread in severely immunodeficient patients (especially during severe neutropenia). Antiviral therapy (aciclovir or valaciclovir) is started as soon as the first vesicles appear.
    • Antiviral treatment Shingles (Herpes Zoster) for herpes zoster is always indicated in patients with cancer with the exception of cases where more than 3 days has elapsed since the emergence of the first vesicles and several days since the emergence of new skin lesions.

Cytomegalovirus (CMV) Cytomegalovirus Prophylaxis with Antiviral Agents for Solid Organ Transplantation, Pre-Emptive Antiviral Treatment to Prevent Cytomegalovirus Disease in Solid Organ Transplant Recipients

  • CMV is a significant cause of infection in patients who have received stem cell or organ transplantation. The virus may reactivate during long-lasting immunosuppressive therapy in patients who are themselves positive for CMV antibodies and those who are negative for CMV antibodies, but who have received a transplant from a CMV antibody positive person. These patients are given pre-emptive therapy with canciclovir or foscarnet. The initiation of pre-emptive treatment is based on follow-up of CMV-DNA-PCR.
  • CMV infection can be treated with ganciclovir, foscarnet or cidofovir.
  • The mortality rate of CMV pneumonia is especially high. It is treated with antiviral drugs combined with intravenous immunoglobulin.

Influenza and other respiratory viral infections

  • Influenza viruses as well as many other respiratory viruses may cause a severe, even fatal disease in severely immunodeficient patients. Neuraminidase inhibitors may be used for the treatment and prophylaxis of influenza Influenza. Neuraminidase inhibitors are effective against both A and B viruses.
  • Among other respiratory viruses especially parainfluenza virus and respiratory syncytial (RS) virus may cause severe infections in immunodeficient patients. Inhaled ribavirin may be tried in the treatment of these infections.

Tuberculosis

  • Remember the possibility of reactivation of tuberculosis in immunosuppressed patients. Previous exposures to contagion of tuberculosis, positive tuberculin test (reaction > 15 mm) or interferon-gamma test and scarring in chest x-ray are suggestive of latent tuberculosis. Risk groups include people who were born before the 1950's, have been exposed to open tuberculosis, have immigrated from areas of high tuberculosis prevalence, have substance abuse problems or are socially excluded.
  • Prophylactic treatment with isoniazid is considered if
    • any of the aforementioned risk factors is detected in a patient undergoing immunosuppressive treatment
    • earlier tuberculosis has not been treated by chemotherapy
    • tuberculosis was treated before the year 1970 (before the time of effective combination chemotherapy).

Pneumocystis jirovecii

  • Secondary or primary prevention is indicated according to the aetiology of immunosuppression. Prophylactic medication is given to all patients who have received either allogeneic stem cell transplantation or transplantation of a solid organ, and to patients with HIV whose CD4 level is below 0.2 × 109 /l. Pneumocystis jirovecii prophylaxis may be considered also for patients who receive long-term cytotoxic chemotherapy that suppresses cell-mediated immunity, and glucocorticoids in large doses.
  • Prophylactic therapy consists of either sulphatrimethoprim Prophylaxis for Pneumocystis Pneumonia in Non-HIV Immunocompromised Patients, given three times a week, or inhaled pentamidine, given once a month. The prophylactic therapy is continued for 6 months after allogeneic stem cell or solid organ transplantation, even longer if the patient receives other potently immunosuppressant drugs, e.g. glucocorticoids or cyclosporin. In patients with HIV the prophylaxis is continued until the CD4 level has permanently risen to 0.2 × 109 /l.
  • The drug of choice for treatment of Pneumocystis jirovecii infection is intravenous sulphatrimethoprim in large doses. For allergic patients, intravenous pentamidine, orally administered atovaquone or a combination of primaquine and clindamycin may be used as alternatives. In severe infections glucocorticoids are added to the regimen.

Fungal infections Treating Oral Candidiasis in Cancer Patients, Routine Versus Selective Antifungal Administration for Control of Fungal Infections in Patients with Cancer, Voriconazole Versus Amphotericin B in Cancer Patients with Neutropenia, Antifungal Therapy in Infants and Children with Invasive Fungal Infections

  • During prolonged and severe neutropenia patients are usually given empiric antifungal medication, if they still have fever after 3-5 days of broad-spectrum antibacterial medication.
    • Nowadays, the ill-tolerated amphotericin B has been replaced by new lipid amphotericin B formulations, by drugs of the echinocandin class (caspofungin) and by broad-spectrum azoles (voriconazole) in the empiric antifungal treatment. They are at least as effective as amphotericin B but the price is high.
    • Fluconazole may in some cases be appropriate for empiric antifungal therapy, but its problems include poor effect in mould fungal infections and the increasing resistance of yeast fungi. The possibility of yeasts resistant to fluconazole should be kept in mind especially in patients with previous long-term fluconazole prophylaxis.
  • Voriconazole is the drug of choice in the treatment of confirmed aspergillosis.
  • Drugs of the echinocandin class (caspofungin, anidulafungin or micafungin) or lipid amphotericin B are the primary choices in the treatment of yeast infections resistant to fluconazole.

References

  • Pappas PG, Kauffman CA, Andes DR et al. Executive Summary: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;62(4):409-17. [PubMed]
  • Freifeld AG, Bow EJ, Sepkowitz KA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011;52(4):e56-93. [PubMed]
  • Davies JM, Lewis MP, Wimperis J et al. Review of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen: prepared on behalf of the British Committee for Standards in Haematology by a working party of the Haemato-Oncology task force. Br J Haematol 2011;155(3):308-17. [PubMed]
  • Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46(3):327-60. [PubMed]
  • Cornely OA, Maertens J, Winston DJ et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356(4):348-59. [PubMed]
  • Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34(6):730-51. [PubMed]
  • Herbrecht R, Denning DW, Patterson TF et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347(6):408-15. [PubMed]
  • Davies JM, Barnes R, Milligan D et al. Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. Clin Med (Lond) 2002;2(5):440-3. [PubMed]
  • Dykewicz CA, Centers for Disease Control and Prevention (U.S.)., Infectious Diseases Society of America. et al. Summary of the Guidelines for Preventing Opportunistic Infections among Hematopoietic Stem Cell Transplant Recipients. Clin Infect Dis 2001;33(2):139-44. [PubMed]

Evidence Summaries ⬆