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.
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.
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.
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).
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 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.
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.
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.
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.
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.
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 sulphatrimethoprimProphylaxis 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.
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.
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