Febrile neutropenia

Febrile neutropenia, or “neutropenic fever,” is a condition in which the level of neutrophils in human blood plasma drops quite suddenly and in a very severe form (less than five hundred).

The progression of this condition is life-threatening.

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Causes febrile neutropenia

The patient's serious condition and the likelihood of even greater health problems, expressed by complications of bacterial and infectious genesis, directly depend on the level of neutrophils in the serum. Low levels of these blood cells from the leukocyte group determine the severity of neutropenia. The causes of febrile neutropenia can be:

• Consequences of cytostatic chemotherapy, which was carried out in connection with the diagnosis of leukemia.
• Somewhat less frequently after a similar procedure, but in connection with the diagnosis of cancerous neoplasms in other affected areas.
• Very rarely, there have been cases of the disease reported after radiation therapy.
• Congenital pathologies. For example, such as:
  • Neutropenia is cyclical.
  • Congenital immunodeficiency.
  • Agranulocytosis is a complete or partial absence of neutrophils.
  • Myelocachexia is a congenital inability of neutrophils to leave the bone marrow.
  • Dyskeratosis is a physiological disorder that causes a disruption in the keratinization process, affecting some cells of the epidermis.
• An infection whose localization was not established in a timely manner due to the fact that there was no response of the patient's body to the irritation. But in the absence of a response, the inflammatory process itself is quite severe. It has a high rate of spread, leading to a fatal outcome.
• Acute pharyngitis or urethritis.
• Febrile neutropenia can be caused by anaerobic microorganisms (for example, clostridia, Bacillus fragilis or Pseudomonas aeruginosa), as well as streptococci, staphylococci, microscopic fungi, Candida spp. Very rarely, but there were still cases when the "provocateur" of the pathology was cytomegalovirus or herpes virus.

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Symptoms febrile neutropenia

The pathological condition manifests itself very quickly. A visual reaction, expressed by symptoms, can appear literally in a matter of hours. There are cases when neuropenia developed within tens of minutes. Symptoms of febrile neutropenia:

• Against the background of a sharp drop in the absolute number of neutrophils (this is an indicator less than 500) or granulocytes (this is an indicator less than 1000), a sharp increase in the patient's body temperature to 38 °C or more is observed.
• A general decrease in tone throughout the body, up to and including severe asthenic syndrome.
• Fine tremor.
• Increased heart rate.
• A decrease in blood pressure. This manifestation can lead to shock or cardiovascular collapse.
• Heavy sweating may occur.

Based on the above, we can briefly conclude that febrile neutropenia is a symptom of exclusion, the diagnosis of pathology is stated without pathognomonic symptoms. If it is possible to subsequently determine the inflammatory focus, then the diagnosis is clarified and corrected. For example, we may be talking about developing sepsis of bacterial etiology or pneumonia.

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Febrile neutropenia in cancer patients

Persons with a history of oncology of any localization belong to the risk group for infection. Such patients have a significantly higher percentage of purulent-inflammatory complications than patients not burdened with such pathology. This risk of infection in such patients largely depends on the nature of the oncological disease, its localization, severity of the course, as well as some factors predisposing to it. Based on this, febrile neutropenia in oncological patients occurs much more often than in patients with other diseases.

After bone marrow transplantation and immunosuppressive treatment, people diagnosed with hemoblastosis (tumors developing from hematopoietic cells) very often experience granulocytopenia (a decrease in the number of neutrophils (granulocytes) in the blood). There is also a suppression of the process of capturing blood and tissues by special cells (phagocytes), as well as the destruction of pathogens and dead cells. This imbalance leads to a violation of humoral and/or cellular protection. This significantly weakens the body, making it "easily accessible" to pathogenic microorganisms.

Febrile neutropenia in cancer patients with solid tumors is much less common, since immunosuppression after cytostatic therapy is poorly expressed. Granulocytopenia in such a clinical picture manifests itself for a short time, the probability of infectious damage is insignificant, but it cannot be completely excluded. The patient can also become infected as a result of natural obstruction: artificial or congenital defect of anatomical membranes, consequences of the use of shunts, catheters, prostheses, as well as with insufficient functioning of receptors of the central nervous system. But such damage, as a rule, is not accompanied by any significant infection.

The longer and more severe the pathology, the higher the risk of infection. But the considered indicator can also be influenced by the drugs chosen for therapy, the frequency of doses during chemotherapy treatment.

Some preferential localization of infection foci in patients suffering from hemoblastosis has also been determined: about 34% of infection cases are due to blood flow damage; 22% affect the pharynx, larynx and oral cavity. About 13% are respiratory diseases, mainly pneumonia, of which approximately one percent are sinusitis. The same percentage (13%) is infection of soft tissues and skin epidermis. About seven percent are damage to the gastrointestinal tract, five percent are phlebitis and intravascular catheters. About three percent are due to infection of the urinary system, all other cases make up about two percent. At the same time, in more than half of the cases, it was not possible to determine the localization of the inflammation focus.

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Diagnostics febrile neutropenia

Even the slightest suspicion of this pathological condition requires urgent comprehensive examination. Diagnosis of febrile neutropenia includes:

• Urine and feces testing is mandatory. The test results may show the presence of an inflammatory process in the patient's body (increased ESR, C-reactive protein).
• Clinical analysis of blood samples.
• Visual examination, using the necessary instrument, of the nasopharynx and pharynx.
• Laboratory examination of vomit and pulmonary or other sputum.
• Analysis of other biological fluids of the patient.

• A study to detect and establish the nature of bacteria isolated from patient material.
• Bacterioscopic examination is a method of examining liquid smears applied to a glass slide.
• Palpation of the lymph nodes.
• Auscultation and chest x-ray.
• Examination of the skin and visually accessible mucous membranes.

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Treatment febrile neutropenia

If the specialist has even the slightest suspicion of the pathology in question and the necessary diagnostic measures have been carried out, treatment of febrile neutropenia begins immediately, even in the absence of a specific etiology of the disease and eradication of the pathogen.

Empirical antibiotic therapy is administered. In this case, broad-spectrum antibiotics are preferred.

The classic combination therapy is the use of an antifungal drug and three antibiotics. It is worth noting that this approach effectively covers almost the entire range of possible pathogens of infectious diseases. For example, such a complex of drugs equally effectively suppresses both streptococci, anaerobic microorganisms, and staphylococci.

If the pathogen is not yet known for certain, and, naturally, the sensitivity to a specific antibiotic has not been determined, then combinations are introduced into the initial treatment protocol, an example of one of which is given below.

1. Medicines belonging to the aminoglycoside group (antibiotics of the second or third generation are mainly prescribed). These include, for example, amikacin or gentamicin.

A highly active drug that effectively inhibits aerobic gram-negative bacteria and negatively affects bacterial protein synthesis, gentamicin is administered to the patient intramuscularly or intravenously (the route of administration is determined by the attending physician). An adult patient is given a single dose of the drug at a rate of 1–1.7 mg per kilogram of the patient’s weight, the daily amount is 3 to 5 mg per kilogram of weight. The drug is administered two to four times a day. The duration of treatment is seven to ten days. For children who are already two years old, the dose is calculated based on the following indicator: 3–5 mg/kg, divided into three doses. For children under two years old, the daily dose of the drug is 2 to 5 mg/kg, divided into three doses throughout the day. For newborns and premature babies, the same daily dosage is divided into two doses.

The drug should not be prescribed in case of hypersensitivity to gentamicin and other aminoglycoside antibiotics, as well as during pregnancy and breastfeeding, severe renal failure or auditory neuritis.

The powerful semi-synthetic antibiotic amikacin is administered by drip or jet. The method of administration is intravenous or intramuscular every eight hours at 5 mg per kilogram of the baby's weight or after 12 hours, but at a dosage of 7.5 mg per kilogram of the patient's body weight. The maximum amount of the drug that can be used during the day is 15 mg per kilogram, but not more than 1.5 g per day. The duration of the treatment course in case of intravenous administration is three to seven days, in case of intramuscular administration - from seven to ten days.

The starting dose of the drug for premature babies is 10 mg/kg, then 7.5 mg/kg. The dose is taken after 18 hours or a day. For newborns, the dosage is the same, and the interval between doses is 12 hours. Dose adjustments are required if the patient has a history of renal failure.

It is not recommended to take this medicine in case of hypersensitivity to gentamicin and other aminoglycoside antibiotics, as well as during pregnancy and breastfeeding, severe renal failure or auditory neuritis.

2. The initial treatment protocol must include aminopenicillin-protected inhibitors. For example, ampicillin-sulbactam or potassium amoxicillin-clavulanate can be used.

The drug potassium amoxicillin-clavulanate is prescribed orally, intramuscularly. The amount of the prescribed drug is calculated in terms of amoxicillin. The regimen and doses are taken strictly individually. They depend on the severity of the pathology, the location, the name of the identified pathogen and its sensitivity to chemical compounds. The dose is prescribed one-time depending on the patient's age.

• newborns up to three months – daily amount – 30 mg per kilogram of the baby’s weight, divided into two doses.
• Children over three months old – daily dose – 25 mg per kilogram of the baby’s weight, divided into two doses (mild infection) or 20 mg/kg three times a day. For severe infection, 45 mg/kg, divided into two doses or 40 mg/kg three times a day.
• adolescents over 12 and adult patients: 0.5 g twice a day or 0.25 g three times during the day.

The maximum amount of the substance administered per day is 0.6 g; for children under 12 years of age, the daily maximum is 10 mg per kilogram of the patient’s weight.

This drug is contraindicated for use in infectious mononucleosis, jaundice, phenylketonuria (a disorder of amino acid metabolism, primarily phenylalanine), liver dysfunction, and individual intolerance to cephalosporins and other beta-lactam drugs.

3. A third-generation cephalosporin or carbapenem is required. Ceftazidime or ceftriaxone, meropenem or imipenem may be prescribed.

The powerful broad-spectrum antibiotic ceftriaxone is given either intravenously or injected into a muscle.

The daily dosage for adult patients and adolescents over 12 years of age corresponds to figures from 1 to 2 g once or 0.5 - 1 g twice a day (every 12 hours). The daily dose should not exceed 4 g.

For newborns up to two months old, the drug is administered at a rate of 20 to 50 mg per kilogram of the infant's weight.

For small children under 12 years of age, the daily amount is calculated from 20 to 80 mg per kilogram of the baby's weight. For children whose weight exceeds 50 kg, the adult dose is prescribed.

If the calculated dosage is 50 mg/kg, ceftriaxone is administered by intravenous infusion over half an hour. The duration of treatment is determined by the doctor depending on the severity of the pathology.

The drug is not prescribed in case of hypersensitivity to the components of the drug or other penicillins, cephalosporins, carbapenems.

Another optimal combination of drugs for the starting period can be called:

• A single potent, broad-spectrum beta-lactam antibiotic that belongs to one of the groups: third-generation cephalosporins, aminopenicillin protective inhibitors, or carbapenems.
• Similar to the protocol proposed above, one aminoglycoside drug is administered.
• And also fluoroquinolones of the III-IV generation. Of the chemical compounds belonging to these drugs, one can name sparfloxacin or moxifloxacin.

Sparfloxacin is administered orally in the morning once. The first day - 0.4 g, then 0.2 g. The duration of the treatment course is prescribed by the attending physician and adjusted depending on the severity of the pathology, but usually lasts ten days. In case of renal failure, the dosage of the drug is reduced.

Sparfloxacin is contraindicated in case of hypersensitivity to its components, history of glucose-6-phosphate dehydrogenase deficiency, predisposition to epileptic seizures, and acute renal failure.

Strong antifungal drugs are required. This may be fluconazole or ketoconazole; to enhance the pharmacodynamics of the antibacterial drugs used, it is recommended to administer metronidazole in parallel.

Fluconazole is administered orally in capsule form. Depending on the specific pathogen, the amount of the drug is prescribed in slightly different dosages, but on average, as a rule, the starting amount is 0.4 g, subsequently the quantitative administration can be reduced to 0.2 g or remain unchanged. The drug is administered once a day. The duration of therapy is six to eight weeks.

The drug should not be prescribed if the patient has a history of increased intolerance to the components of the drug, as well as to women during pregnancy and lactation, and to children under five years of age.

The antiprotozoal and antimicrobial drug metronidazole is used in a dosage depending on the source of the lesion. The dose is prescribed in numbers of 0.25 - 0.5 g, taken twice a day. The duration of therapy is five to eight days. If medically necessary, the treatment can be repeated with a break of three to four weeks. The daily amount of the drug administered can range from 0.75 to 1 g.

Metronidazole is not recommended for use if the patient has a history of leukopenia, liver dysfunction, organic damage to the central nervous system, individual intolerance to the components of the drug, pregnancy and breastfeeding.

If there is a suspicion that the causative agent of the inflammatory process is enterococci or staphylococci, it is better to immediately include vancomycin in the treatment protocol, replacing it with drugs of the aminoglycoside group, since their combined use is undesirable, based on the fact that such a tandem mutually enhances the nephrotoxicity of chemical compounds.

Vancomycin is administered intravenously to the patient. An adult patient receives 0.5 g every six hours or 1 g every 12 hours. To prevent the patient from provoking collapse reactions, the stated volume should be administered approximately every hour. For small patients, the daily dosage is prescribed at the rate of 40 mg per kilogram of the child's weight. The rate of administration is similar. If the patient suffers from problems with urine excretion (renal failure), the dosage is adjusted taking into account creatinine clearance.

In some cases, the drug is prescribed orally, then the adult daily dose of the drug is administered from 0.5 to 2 g, divided into three to four doses, for small patients - 40 mg per kilogram of the child's weight, divided into three to four doses.

The drug in question is not recommended for use in cases of auditory nerve neuritis, individual intolerance to the components of the drug, during the first trimester of pregnancy and during breastfeeding.

The maximum amount of the drug allowed to be taken during the day should not exceed 4 g.

If microflora of the Pseudomonas type is reasonably suspected as the source of pathology, it is better to immediately prescribe the drug ticarcillin or something similar to it.

The method of administration and dosage of this medicine is prescribed by the doctor, based on the overall clinical picture and age of the patient. The drug should not be administered if the patient has a history of hypersensitivity to ticarcillin or beta-lactam antibiotics.

If the pathogen has been identified, then the therapy is adjusted based on this knowledge. Intensive three-day therapy has been administered, and the patient's condition has not improved - amphotericin B is introduced into the treatment. When it is prescribed, aminoglycosides are discontinued to prevent the development of kidney damage.

In case of febrile neutropenia diagnosis, administration of antipyretic drugs is not allowed. The consequence of their use changes the clinical picture of the disease, not allowing to evaluate the actual dynamics of therapy.

Prevention

People with a low level of immune protection are at increased risk of invasion by pathogenic flora, which, depending on the localization, causes various infectious and inflammatory diseases. To reduce the risk of damage, it is necessary, first of all, to take care of the immune system. Necessary prevention of febrile neutropenia:

• Dietary adjustments are necessary.
• The diet must include vegetables and fruits rich in vitamins and minerals.
• Regular ventilation of living spaces and their wet cleaning.
• A complete rest.
• Light physical activity and walks in the fresh air.
• It is necessary to minimize contact between medical personnel who have had symptoms of a viral cold and patients with a history of immunodeficiency.
• General personal hygiene rules should not be ignored.
• Cleaning and washing of toilets, sinks and other surfaces should be carried out using disinfectant solutions.
• Dishes of patients with a weakened immune system, after washing, should be processed in an oven at a temperature of 70 - 80 ºС.
• Fresh fruits and vegetables must be thoroughly washed or cooked before being processed or eaten.
• It is better to sterilize milk rather than pasteurize it.
• Prevention of febrile neutropenia with antimicrobial drugs.
• Selective decontamination using adsorbent drugs (activated carbon).
• Drug prophylaxis of febrile neutropenia after chemotherapy using dicarbamine.

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Forecast

The immediate and long-term prognosis of febrile neutropenia directly depends on the severity of the lesion and the timeliness of the adequate therapy. The prognosis of a benign, mild course is favorable in almost all cases. If the pathology is caused by a malignant neoplasm, aggravated by lymphocytopenia, the prognosis is less favorable.

About 21% of patients with the pathology in question, which developed against the background of cancerous diseases of various localizations, expect an unfavorable prognosis.

Congenital febrile neutropenia may have a good prognosis only in the case of lifelong prophylactic therapy or successful bone marrow transplantation. The only exception may be congenital neutropenia of a chronic nature and benign etiology, which has a low probability of infectious contamination.

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