Granulocyte deficiency is a common complication in the treatment of hematologic diseases and malignancies. The following is a brief discussion of preventive and therapeutic measures for patients with granulocyte deficiency in terms of infectious fever.
1. Prevention of granulocyte deficiency infections.
The prevention of granulocyte deficiency co-infection is important. The pathogenic microorganisms that cause infectious fever in granulocyte deficient patients may be microorganisms residing in the body or transmitted from outside. Therefore, relevant preventive measures include proper isolation from the outside world, protection of body barrier and drug prevention.
(1) Appropriate isolation: This includes environmental protection, dietary hygiene, etc. to reduce infection caused by cross-contamination of air, food and personnel. Specific measures for environmental protection include no contact with animals and infected patients, fewer visitors, single-person wards if possible, non-laminar flow wards with good ventilation, no flowers or plants in the rooms, laminar flow beds or laminar flow wards for those who have been absent for a long time, and hand hygiene for health care workers in contact with patients. Diet should be mainly cooked, raw fruits should be peeled and fresh, no cold dishes and pickled products.
(2) Protection of body barrier: pay attention to personal hygiene and strict disinfection of invasive operations. Keep the oral cavity and perianal mucosa clean by rinsing the mouth after eating and taking a sitz bath after defecation; avoid anal fissures caused by dry stools with appropriate diet and laxative drugs. Pay attention to the clean care of the skin, check the central venous catheter, disinfect the wound and change the dressing daily; conduct invasive examinations such as venipuncture or bone puncture with strict aseptic operation.
(3) Drug prevention of infection: Patients who have had invasive deep fungal infections need to apply antifungal drugs for secondary prevention. The 2010 edition of the IDSA guideline considers fluoroquinolone as a preventive drug for high-risk patients with granulocytes <0.1×109/L or granulocyte deficiency longer than 7 days, but the high resistance rate of fluoroquinolone in China is not suitable for the prevention of bacterial infection in patients with granulocyte deficiency. However, the high resistance rate of fluoroquinolone is not suitable for the prevention of bacterial infection in high-risk patients with granulomatous deficiency in China, while piperacillin is more suitable for the prevention of bacterial infection in high-risk patients with granulomatous deficiency in China because of its antibacterial spectrum and price.
2. Pre-treatment evaluation.
It not only helps to determine the patient’s treatment plan, but also helps to predict the patient’s disease regression, the incidence and risk of complications. Once a patient with granulomatous deficiency develops infectious fever, the relevant evaluation should be improved as soon as possible and anti-infective treatment should be administered as soon as possible.
(1) The examinations that should be done for pre-treatment evaluation include.
(1) careful physical examination for the presence of infectious lesions, as well as assessment of vital signs to understand the severity of infection.
(ii) Emergency blood tests, liver and kidney function and electrolytes.
③ Pathogenic examination: peripheral blood and central venous line drawing for blood culture and smear and culture of swab or puncture fluid (material) and secretion/excretion from suspected infected site, G test, GM test.
(iv) Testing of infection indicators C-reactive protein and calcitoninogen.
(6) Chest X-ray, and if possible, high-resolution CT examination. High-resolution CT can detect the presence of pulmonary infection in many patients with granulomatous fever with normal chest films; if other parts of infection are suspected, corresponding imaging examinations can be performed, such as abdominal ultrasound, sinus CT, etc.
(2) Risk assessment before treatment: Since most patients with granulomatous fever do not have signs of infection and positive pathogenic microorganisms, risk assessment is helpful to select a relatively appropriate treatment strategy. The IDSA guidelines recommend the Multinational Association for Supportive Care of Cancer (MASSC) scoring system, and those with a cumulative score of ≥12 are considered low-risk patients.
(i) Febrile neutropenic burden is the general clinical status of patients affected by the febrile neutropenic phase.
② Chronic obstructive pulmonary disease is defined as active chronic bronchitis, emphysema, and reduced exertional whistle volume with febrile neutropenic manifestations requiring oxygen therapy and/or steroid and/or bronchodilator therapy.
③Previous fungal infection is defined as having a confirmed fungal infection, or a suspected fungal infection treated empirically.
3. Empirical initial treatment.
Patients with granular deficiency have poor resistance and the infection is easy to spread and aggravate the disease. The initial empirical anti-infective treatment plan should be decided as soon as possible according to the clinical risk factors of the patient and the pathogenic microbial spectrum of the region, and attention should also be paid to strengthening symptomatic treatment such as antipyretic, maintaining hydropower balance and nutrition support.
(1) Selection of basic antibacterial drugs: As the degree of granulomatous deficiency deepens and lengthens, the chance of bacterial infection increases significantly, and the initial empirical treatment of granulomatous deficiency with fever mainly targets bacterial infection. Bacterial infections are mostly potential sources of disease in vivo, mostly entering the body through injuries on the skin or mucosal surfaces, especially Gram-negative drug-resistant bacteria are often the main cause of granular deficiency infections. The IDSA recommends ceftazidime, cefepime, carbapenems and piperacillin-triazobactam for the initial empirical treatment of patients with granulomatous defects with fever. We feel that carbapenems should be preferred for high-risk patients and cefepime or piperacillin-triazobactam can be used as the basic initial empirical treatment for low-risk patients.
(2) Combination of drugs or not: Whether or not to combine drugs should be determined specifically based on clinical factors. Combination of aminoglycosides may be considered for patients with G-bacteremia or pulmonary infection; combination of metronidazole may be considered if there are clear signs of abdominal or pelvic infection.
The addition of anti-G+ bacteriophages may be considered when the following factors are present.
① skin or soft tissue infections.
(ii) Severe mucositis.
(iii) suspected catheter-related infection.
④ imaging showing pneumonia.
⑤ the presence of methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, or penicillin-resistant Streptococcus pneumoniae colonization.
(vi) Positive blood culture for G+ bacteria.
(7) Evidence of severe sepsis or infectious shock.
(3) Application of hematopoietic growth factors: granulocyte colony-stimulating factor (G-CSF) can shorten the duration of granulocytopenia, the duration of antimicrobial therapy and hospitalization, but it should be noted that G-CSF also has an immune negative regulatory effect. G-CSF is recommended for high-risk patients with severe granulomatous defects or granulomatous defects of long duration, but is not recommended for the routine treatment of confirmed fever and granulomatous defects.
(4) Granulocyte infusion: Granulocyte infusion is still controversial as a treatment for granulomatous deficiency co-infection.
The main reasons for its limitation are.
(i) short survival time of mature granulocytes.
②The number of collected granulocytes is difficult to meet clinical needs.
③The activity and function of granulocytes can be affected during the isolation and collection process.
④It may lead to complications such as fever and rejection.
However, for high-risk granulocyte deficiency with severe infection, especially bacterial infection, granulocyte infusion may still have some value.
4. Re-evaluation after empirical treatment.
Patients with granulocyte deficiency with infectious fever should be evaluated for efficacy 2-4 days after either empirical treatment or replacement antibiotic therapy, and the next step of management should be decided according to the efficacy.
(1) Effective empirical treatment: The main criteria are temperature decrease, stable disease and clinical signs improvement. It should be noted that for patients with severe granulomatous deficiency, even if empirical treatment is effective, the patient may still have fever, but the peak and frequency of fever should be significantly reduced, and the condition should not deteriorate. Patients with effective empirical treatment should continue the relevant treatment until the temperature is normal for 3 days and the granulocytes are greater than 0.5×109/L. The drug can be discontinued.
(2) Ineffective empirical treatment: This is a difficult problem often encountered in clinical work, and the main reasons are.
(1) drug dosage is not standardized resulting in poor drug concentration at the site of infection.
(2) drug-resistant bacterial infections.
③ Mixed non-bacterial infections, such as fungal, tuberculosis or viral infections, etc.
(4) Poor drainage or non-removal of necrotic tissue from the infected site.
⑤ catheter-related infections.
In cases where empirical treatment is ineffective, the initial assessment must be dynamically reviewed and analyzed, along with reassessment of the patient’s condition, examination of possible sites of infection and pathogenic microorganisms, and careful review of empirical treatment protocols for standardization. In cases where there is still no clear evidence of the site of infection and etiology, if the empirical therapeutic agent is cefepime or piperacillin-triazobactam, it should be replaced with a hydrocarbon-enzyme class; as there are partial differences in the resistance mechanisms of different hydrocarbon-enzyme class drugs to Pseudomonas aeruginosa, and also in recent years, CHINET surveillance has suggested a significant increase in the detection rate and resistance rate of domestic immobile bacteria, immobile bacteria and P. aeruginosa If the empirical treatment is hydrogenase alkenes, it is recommended to switch to another type of hydrogenase alkenes, and can be combined with drugs containing sulbactam such as cefoperazone/sulbactam. In addition, the proportion of Gram-positive bacterial infections has been increasing in recent years due to the widespread use of broad-spectrum antibiotics targeting mainly Gram-negative bacteria, the routine use of central venous cannulation and mucosal injury due to radiotherapy. Therefore, the need for empirical addition of anti-G+ bacteria drugs should be carefully considered along with the switch of anti-G- bacteria drugs.
Re-evaluation is required 2-4 days after the change of treatment, and those who are effective continue the relevant treatment until discontinuation; if the change of medication is still ineffective, it is necessary to review the lung CT and other examinations, and strengthen the etiological examination, because with the prolongation of granulocytopenia and the application of broad-spectrum antimicrobial agents, mixed infections increase, which can be both a mixture of multiple bacteria and a mixture of bacteria, fungi, viruses and tuberculosis. At this time, antifungal drugs should be added, and azoles, echinocandins or polyenes can be used according to the patient’s condition, but if a clinical diagnosis of Aspergillus infection is proposed, voriconazole is preferable. The need to remove the central venous placement should be considered along with the active search for the foci of infection and the pathogenic microorganisms.
(3) About step-down: Patients with granulomatous deficiency complicated by infectious fever mostly have unknown foci of infection and pathogenic microorganisms, how to step down is a noteworthy issue, and inappropriate step-down treatment has the risk of lethal infection. Although broad-spectrum antibiotic treatment of granulomatous fever with infectious fever has the risk of causing dysbiosis that leads to multiple infections and inducing drug-resistant bacteria, in general, granulomatous fever with unknown cause of fever should not be routinely step-down to antimicrobials, and step-down therapy is usually limited to patients with a clear pathogenic microorganism or site of infection. For example, G- bacteria producing ESBLs need to be treated with carbapenems, while carbapenemase-producing bacteria need to be treated with polymyxin or tigecycline instead; G+ cocci need to be treated with vancomycin or linezolid if they are methicillin-resistant Staphylococcus aureus, while vancomycin-resistant enterococci need to be treated with linezolid.
Therefore, patients with granulocyte deficiency complicated by infection should be evaluated for their condition as soon as possible before treatment and examined for possible sites of infection and tested for pathogenic organisms. Antimicrobial therapy should be administered early, promptly, and reasonably based on the epidemiology of local bacteria, and the efficacy should be judged promptly after 2-4 days to decide how to adjust the treatment. Patients with evidence of pathogenesis or foci of infection may be treated in descending steps as appropriate; in the case of unexplained fever, anti-infective therapy is administered until temperature is normal for 3 days and granulocytes are above 0.5 × 109/L.