Infectious complications in cancer patients

Infectious complications are the most common causes of oncological patients entering the ICU. Both the tumor itself and its treatment (chemotherapy, radiation therapy, surgery) change the spectrum of prevalent pathogens (opportunistic, atypical pathogens), the clinical picture of habitual infections (absence or change of usual symptoms), the severity of the course of the infectious process (fulminant sepsis) e. The article outlines the main differences in the diagnosis and treatment of infections in cancer patients. Optimal attraction to the differential diagnosis of a specialist who conducted antitumor treatment.

[1], [2], [3], [4], [5]

Special clinical situations

Bacteremia

The risk of developing bacteremia in patients with cancer directly depends on the presence and duration of neutropenia. The detection of bacteremia in most cases is the reason for modifying the initial therapy. Detection in blood cultures of coagulase staphylococci and corynebacteria is often due to contamination. However, in patients with immunosuppression (especially in patients with central venous catheters), these skin saprophytes can cause bacteremia. When sowing coagulase staphylococci in case of doubt (bacteremia or contamination), the decision to change antibiotic therapy in a clinically stable patient can be postponed until the results of a re-examination are obtained, which is due to the low virulence of the pathogen. On the other hand, corynebacteria and Staphylococcus aureus are highly pathogenic microorganisms, and obtaining the growth of the pathogen from even one blood sample requires the addition of vancomycin to initial antibiotic therapy.

If a gram-negative pathogen is detected, the decision is made depending on the clinical situation. When the pathogen is isolated from a blood sample obtained before the beginning of empirical antibacterial therapy, the initial regimen of therapy is used until the data on the sensitivity of the causative agent are obtained for the entire time, while the patient's condition remains clinically stable. If it worsens or the gram-negative pathogen is isolated from the blood already against the background of empirical antibiotic therapy, an immediate change in antibiotic therapy is necessary.

[6], [7], [8], [9], [10], [11], [12]

Patients with vascular catheters

Most infections in the field of catheter insertion are cured without removing it by prescribing antibiotics. Prior to receiving data on sensitivity to antibiotics, the drug of choice is vancomycin. In case of tunnel infection, in addition to prescribing antibiotics, removal of the catheter is also required. When bacteremia associated with a catheter is prescribed antibacterial therapy, the issue of removing a non-implantable catheter in a patient with a stable clinical condition remains at the doctor's discretion. Implantable catheters can be left on the background of antibiotic therapy and daily blood cultures. Removal is indicated if bacteraemia persists for more than three days or when a second episode of bacteremia is caused by the same pathogen. Catheters should also be removed in all patients with signs of septic shock when high-resistant pathogens (fungi, Bacillus, etc.) or septic thrombophlebitis are detected.

Sinusitis

In immunocompetent patients respiratory bacterial pathogens are usually responsible for the development of sinusitis. In patients with neutropenia or other types of immunosuppression, Gram-negative pathogens and fungi are more common. In the case of sinusitis in a patient with neutropenia, it is necessary to prescribe drugs of the first line of treatment for neutropenic infection. If there is no improvement within 3 days, therapeutic and diagnostic aspiration of the contents of the sinuses is recommended. When detecting fungal pathogens, therapy with high doses of amphotericin B is performed at 1-1.5 mg / (kilogram). If it is impossible to conduct aspiration, therapy is prescribed empirically. It is necessary to carry out a surgical sanation, as against the background of neutropenia only medication therapy rarely leads to a cure.

Pulmonary infiltrates

Pulmonary infiltrates in patients with immunosuppression are classified into early focal, refractory focal, late focal and interstitial diffuse.

Early focal infiltrates. Under the early mean infiltrates, appearing during the first episode of neutropenic fever. Infection is most often caused by bacterial pathogens, such as Enterobactenaceae, Staphylococcus aureus. At occurrence of the centers it is necessary to perform at least two cultures of blood, urine and sputum.

Refractory focal infiltrates cause atypical pathogens Legionella, Chlamydia, Mycoplasma, Nocardia and Mycobacterum, as well as viral and fungal pathogens. In many cases, an invasive procedure is necessary to establish the diagnosis (BAL, needle aspiration, open lung biopsy).

Late focal infiltrates occur on the seventh or more day of empirical therapy in patients with persistent neutropenia. The most frequent causative agent of late infiltrates against the background of persistent neutropenia is Aspergillus. As in the case of refractory pneumonia, late infiltrates are caused by infection (or superinfection) caused by bacteria, viruses and protozoa that are resistant to the original scheme.

Interstitial diffuse infiltrates are caused by a significant number of pathogens. The diffuse process is a reflection of the progression of bacterial infection (Mycobacterium tuberculosis, atypical mycobacteria) or of another nature (Strongyloides stercoralis, Pneumocystis carinii). For diagnosis, BAL is recommended, which is highly informative for infiltrative pulmonary disease caused by pathogens such as Mycobacterium tuberculosis, Pneumocystis carinii and respiratory viruses. For foci with a diameter of more than 2 cm, the pathogen can be detected in 50-80% of cases, while in smaller foci - only 15%. The most accurate method of diagnosis is open lung biopsy.

Neutropenic enterocolitis

Patients with prolonged neutropenia have a high risk of developing neutropenic enterocolitis. The disease is caused by the massive penetration of the intestinal microflora through the damaged mucosa into the intestinal wall and further into the systemic bloodstream. The clinic is often similar to the clinic of an acute abdomen (fever, abdominal pain, peritoneal symptomatology, diarrhea with an admixture of blood or paralytic ileus). Soreness and tension are more often localized in the projection of the cecum, but it can also be diffuse. Systemic infection with neutropenic enterocolitis is often characterized by fulminant flow, because it is caused by highly pathogenic Gram-negative microorganisms (Pseudomonas, Enterobactenaceae). Sometimes the first signs of developing enterocolitis are rapid deterioration of the patient's condition and septic shock. Surgical treatment in most cases only worsens the condition of patients, and therefore patients who have symptoms of an acute abdomen with neutropenia should be examined by the most experienced surgeon. The patient's chance of remaining alive largely depends on the timeliness and correctness of the diagnosis. The main sign that allows to diagnose the development of neutropenic enterocolitis is a significant thickening of the intestinal wall (terminal sections of the ileum, blind or ascending colon) according to ultrasound or CT. In addition, sometimes a moderate amount of free fluid is observed in the abdominal cavity adjacent to the affected intestine and the formation of an inflammatory conglomerate in the ileum. In connection with the relative scarcity of this pathology, the clinician should focus the attention of the radiologist on the area of interest and the measurement of the thickness of the intestinal wall.

Treatment of neutropenic enterocolitis is mostly conservative. Due to the severity of the patient's condition, there is often no chance of a "second attempt", and empirical antibiotic therapy must influence the entire spectrum of potential pathogens, imipenem + cilastatin, or a combination of meropenem or cefepime with metronidazole, is most commonly used in this situation. In case of a serious condition of the patient, a picture of septic shock to this therapy, amikacin is added at 15 mg / kg per day and vancomycin 1 g 2 times a day. With the development of paralytic ileus, nasogastric intubation is necessary for decompression. It is highly desirable to prescribe cytokines (colony-stimulating factors of G-CSF), since with neutropenic enterocolitis the restoration of the normal level of neutrophils is important for a favorable outcome.

Surgical treatment is currently shown only to a small group of patients:

• Continuing gastrointestinal bleeding after resolution of neutropenia, thrombocytopenia and correction of the coagulation system.
• The presence of signs of perforation of the intestine into the free abdominal cavity.
• Presence of uncontrolled sepsis.
• Development of a process that in the absence of neutropenia requires surgical intervention (appendicitis, diffuse peritonitis).

When the patient is relatively stable, it is recommended to postpone surgical treatment until neutropenia is resolved, even in the case of delimited localized peritonitis, effusion around the cecum or suspected closed perforation. If necessary, the surgical manual includes resection of the necrotic gut (most often right-sided hemicolectomy) or decompression ileostomy.

Anorectal infections

Anorectal infections in patients with malignant neoplasms pose a threat to life. In patients receiving intensive chemotherapy (the main risk factor), severe anorectal infections are observed in about 5% of cases.

In this regard, it is mandatory to carry out sequential examinations of the anorectal area. The presence of large foci of softening, maceration of the skin is the reason for the immediate appointment of therapy with mandatory antianaerobic activity (ceftazidime + metranidazole or monotherapy with carbapenems). Finger rectal examination of patients is not performed, as it carries an additional risk of infection and bleeding. CT scan is useful when suspicion of spread of infection on the pelvic structures. Indication for surgical treatment is the progression of infection, despite adequate antibiotic therapy, obvious tissue necrosis or the appearance of fluctuations.

[13], [14], [15], [16], [17], [18], [19], [20], [21],

Diagnostics

Anamnestic data are used to quickly identify risk factors for the development of a particular infection. The presence of infectious complications in previous courses of similar therapy predicts the risk of their development with this hospitalization. For example, data on the presence of a history of clostridial colitis should be the reason for an additional examination (stool analysis for Clostridium difficile toxin) in the event of fever and diarrhea. Prior invasive candidiasis or aspergillosis can predict a relapse of the infection during the next neutropenia period.

[22], [23], [24], [25], [26],

Physical examination

In addition to conventional examinations (auscultation, abdominal palpation, etc.), an additional thorough examination of all areas of the body is necessary. The oral cavity and pharynx should be examined (ulcerous defects in stomatitis, odontogenic infection, abscesses in head and neck tumors), areas previously performed biopsies and other invasive manipulations, perineum (paraproctitis, abscesses), areas of the nail plates and adjacent tissues (panaritium). It should be remembered that against the background of immunosuppression, typical signs of infection (reddening, induration, edema, etc.) are poorly expressed even in the case of a significant amount of tissue damage (phlegmon).

Laboratory research

The required diagnostic minimum, regardless of the tests conducted for other indications:

• a complete clinical analysis of blood with a leukocyte formula,
• biochemical blood test (glucose and total protein, bilirubin and creatinine, urea, hepatic enzymes),
• sowing urine before the appointment of antibiotic therapy,
• sowing blood before the appointment of antibiotic therapy (minimum of two points are required to receive blood samples from each lumen of the pulp and paper plant, if available and from the peripheral vein);
• sowing pathological exudates (sputum, pus) and material from potentially infected foci (aspirate from the area of subcutaneous cellulitis).

Instrumental research

Radiography of the chest. In the presence of symptoms of lung injury, CT is preferred, as it allows the detection of pneumonia in 50% of patients who do not have changes with standard radiography.

Ultrasound of the abdominal cavity organs in the presence of complaints, given anamnesis (diarrhea, abdominal pain).

Features of diagnosis and treatment of infection in various clinical situations

[27], [28], [29], [30]

Patients bvz expressed neutropenia

In patients without severe neutropenia (neutrophils> 0.5 × ^{10 9} / L), which do not receive conservative antitumor and cytostatic therapies:

• low degree of immunosuppression,
• the usual or slightly increased severity of infectious complications,
• habitual spectrum of pathogens, which depends on the location of the tumor and surgical intervention,
• the clinical picture of the infectious process is normal,
• The tactics of treatment and examination are typical,
• risk factors for infections obstruction of hollow organs and violation of the integrity of barrier tissues.

Patients with neutropenia

The degree of immunosuppression in patients with neutropenia depends on the level of neutrophils in the blood:

• <1,0х10 ⁹ / l - increased,
• <0.5х10 ⁹ / l - high,
• <0,1U10 ⁹ / l - extremely high.

The most dangerous is neutropenia <0.1 × ^{10 9} / L lasting more than 10 days. The patient is noted for a more severe course of infectious complications, acceleration of dissemination of the pathogen (bacteremia, fungemia is met much more often), and the consequences of "banal" infections can be catastrophic, for example, with gram-negative infection, a two-day delay in prescribing antibiotics leads to the death of> 50% of patients. Infectious agents - more often bacteria, mainly gram-positive, fungi, with prolonged neutropenia, the proportion of fungal pathogens is increased.

The clinical picture of the infectious process is atypical, the absence of cough, sputum and X-ray changes in pneumonia, lack of pyuria in urinary infections and pleocytosis with meningitis, massive phlegmons without pronounced induration and redness, etc. Are smeared. The only symptom of infection, which is observed as often as in patients without neutropenia, is fever. In this regard, with neutropenia febrile fever is a sufficient reason for prescribing antibiotics.

In patients with febrile neutropenia, the neutrophil count is <0.5 × ^{10 9} / L or <1.0 × ^{10 9} / L with a tendency to rapid decline. The tactics of treatment and examination are closely related to the characteristics described above (see anamnesis, physical examination, laboratory / instrumental examination).

Treatment of infection against neutropenia requires mandatory prescription of antibacterial drugs of a wide spectrum of action, which have a bactericidal action against the most dangerous pathogens. Afeuble patients with neutropenia who have signs or symptoms similar to those of the infection also receive antibacterial therapy.

The main differences between the treatment tactics in the presence and absence of neutropenia

Proven infection	Without neutropenia	With neutropenia
Bacteriologically documented (identified pathogen)	Antibiotic therapy according to the pathogen sensitivity spectrum	Antibiotics of a wide spectrum of action with obligatory activity against Pseudomonas acidovorans + antibiotic therapy directed on the resistant pathogen
Clinically documented (identified as the focus of infection)	Antibiotic therapy aimed at the most likely pathogen	Antibiotics of a broad spectrum of action with mandatory activity against Pseudomonas acidovorans +/- antibiotic therapy aimed at the most likely resistant pathogen
Fever of unknown origin (foci and pathogen not identified)	The appointment of antibiotic therapy only with clinical or bacteriological confirmation of infection or extremely serious condition of the patient	Empirical antibiotic therapy with a broad spectrum of action with mandatory activity against Pseudomonas acidovorans

In the case of an infectious process caused by a resistant Gram-negative flora, a combination of the base preparation with an aminoglycoside (amikacin 15 mg / kg once daily IV) is possible. With severe mucosal lesions or suspected catheter sepsis, vancomycin is given 1 g 2 times daily iv. Further modification of antibacterial therapy is desirable in collaboration with a specialist who conducted antitumor treatment.

Algorithm for the most common clinical situations

Clinical situation	Examination and treatment
Preserved against a background of atibiotikoterapii a wide spectrum of action (3-7 days) neutropenic fever without the revealed infectious focus	Re-examination Adding empirical antifungal therapy (amphotericin B 0.5-0.6 mg / kg per day or fluconazole 400 mg per day) If fluconazole was used previously, its replacement with amphotericin B
Return of fever against the background of initially effective therapy after 14 or more days (without the identified focus of infection)	Extremely suspicious in terms of fungal infection Assign empiric therapy with amphotericin B to 0 5-0.6 mg / kg per day Conducting CT In case of suspected infection caused by mold fungi, BAL, biopsy is prescribed. In confirmation of the diagnosis, amphotericin B in high doses (1 , 0-1.5 mg / kg per day)
Persistent or recurrent fever without an identified focus in the background of recovery of neutrophil levels	Possible hepatolyenal candidiasis Conduct ultrasound and / or CT of abdominal organs When detecting foci shows a percutaneous needle biopsy with bacteriological examination
Gram-positive microorganism in the blood obtained before the beginning of empirical antibiotic therapy	Add vancomycin
Gram-negative microorganism in blood obtained before the beginning of empirical antibiotic therapy	If the patient's condition is stable it is necessary to continue the initial antibiotic therapy, in the case of clinical instability, it is necessary to replace ceftazidime (if initially used) with carbapenems to add aminoglycoside. Modification of the regimen according to the sensitivity spectrum of the pathogen should be performed after obtaining data from the bacteriological laboratory
Gram-positive microorganism in the blood obtained during the period of empirical antibiotic therapy	Add vancomycin
Gram-negative microorganism in the blood obtained during the period of empirical antibiotic therapy	To suspect a resistant pathogen (depending on the antibiotic regimen used) If ceftazidime was first used - substitution for carbapenems and addition of aminoglycoside If carbapenems were used initially, then the most likely pathogen may be Pseudomonas Ciprofloxacin and trimethoprim administration is necessary. Further modification of the therapy is conducted to obtain sensitivity data
Necrotic gingivitis	If in the initial therapy was used ceftazidime or cefepime - the probability of anaerobic pathogens is high. It is necessary to replace with carbapenems or add metronidazole to influence a potential anaerobic pathogen
Symptoms of sinusitis	Drainage of sinuses for diagnostic and therapeutic purposes Gram-negative infection (Enterobacteriaceae or Pseudomonas) is probable, with neutropenia> 10 days infection with mold fungi is more likely
New pulmonary infiltrates after resolution of neutropenia	There may be a "manifestation" of the inflammatory response to the old infectious foci If the patient has no symptoms - observation, in the presence of symptoms - BAL fluid and a biopsy to identify the pathogen
Diffuse infiltrates	If the patient receives glucocorticoids - a suspected pneumonia caused by Pneumocystis carinii Possible infections caused by respiratory viruses, bacterial pneumonia and non-infectious causes (hemorrhages, ARDS, toxicity of chemotherapy and radiation) It is highly desirable to conduct BAL in emergency
Acute abdominal pain	Differential diagnosis includes diseases observed outside the period of neutropenia (cholecystitis appendicitis and td) and neutropenic enterocolitis. Antibiotics are required that overlap the intestinal flora and anaerobic pathogens (ceftazim dim or cefepime + metronidazole, or monotherapy with imipenem). If necessary, surgical intervention
Perirrectal infection	Antibiotic therapy is required that overlaps the intestinal flora and anaerobic pathogens (ceftazidime or cefepime + metronidazole, or imipenem monotherapy). If necessary, surgical intervention
Cellulite in the field of catheter insertion	The most likely gram-positive pathogens - the inhabitants of the skin (possibly resistant) It is necessary to add vancomycin
Infection along the course of the catheter (tunnel)	The most likely Gram-positive pathogens - the inhabitants of the skin (possibly resistant) It is necessary to remove the catheter and the addition of vancomycin
Suppuration (detachable) around the catheter	Clear edges, remove exudate Send exudate to bacteriological examination If necessary - remove catheter and antibiotic therapy
Local catheter infection caused by Aspergillus or Mycobacterium	Catheter removal, topical treatment. It may be necessary to excise tissues around the subcutaneous tunnel. Anti-infective therapy, depending on the pathogen
Catheter-associated bacteremia	Add the necessary antibiotic Remove the catheter in case of detection of a highly resistant pathogen (Mycobacterium, Candida albicans) Also removal is indicated with resistance to antibacterial therapy and / or hemodynamic instability
New focuses of infiltration in the period of neutropenia	Resistant bacteria or mold fungi are possible . If BAL fluid or sputum is not informative, empiric therapy with amphotericin B in high doses (1-1.5 mg / kg / day)

Patients with mucosal damage

In patients with mucosal damage, a low degree of immunosuppression, possible development of concomitant neutropenia, increased severity of infectious complications, since the damaged mucosa is a large "wound surface" that contacts highly pathogenic microorganisms and the environment (secrets of the oral cavity, feces, ). The spectrum of pathogens depends on the area of the lesion, with damage to the oral mucosa, mainly gram-positive pathogens are detected, the intestinal mucosa is Gram-negative and anaerobic pathogens.

The clinical picture of the infectious process is common. With severe damage, a fulminant course of systemic infections (streptococcal syndrome, shock with neutropenic enterocolitis) is often observed, which is caused by a large number of pathogens and toxins entering the blood.

The tactics of treatment and examination are related to the characteristics described above (see anamnesis, physical examination, laboratory / instrumental examination). In the presence of signs of damage to the mucous membranes of the oral cavity, oropharynx, esophagus and infection requiring placement in the ICU, it is justified to add to the first line antibacterial therapy of vancomycin. With the development of severe systemic infection against the background of severe intestinal mucosal lesions, the most aggressive antibiotic therapy for carbapenems + aminoglycosides + vancomycin +/- antifungal agent is prescribed.

Patients receiving glucocorticoids

In patients receiving glucocorticoids, a high degree of immunosuppression, and infectious complications are particularly difficult. With long-term administration of drugs, even in relatively small doses (8-16 mg of dexamethasone per day), the probability of developing infectious complications is greatly increased. The causative agents of infection are most often yeast and mold fungi.

Perhaps a little symptomatic current of the usual infectious process, the doctor needs to be wary in terms of diagnosing "unusual" infections.

The tactics of treatment and examination are closely related to the characteristics described above (see anamnesis, physical examination, laboratory / instrumental examination). In case of development of unusual symptoms of the infectious process, it is highly desirable to hire a consultant who has experience in treating patients with atypical infections (hematologist, infectious disease specialist).

Patients after splenectomy

In patients after splenectomy, a high degree of immunosuppression is observed for encapsulated bacteria, and the preventive use of penicillins increases the risk of the presence of resistant pathogens.

After splenectomy, infections caused by encapsulated pathogens occur unusually hard and quickly lead to death.

The tactics for examining patients is usual, it is desirable to obtain data on the preventive use of penicillins. Drugs that are active against encapsulated bacteria of cephalosporins, macrolides, trimethoprim + sulfamethoxazole are mandatory. Penicillins are used only in the absence of preventive therapy.

Patients after transplantation and chemotherapy

In patients who underwent chemotherapy (fludarabine, cladribine, alemtuzumab) and allogeneic bone marrow transplantation, an extremely high degree of immunosuppression, especially with regard to cellular immunity, persisted for months and years after the treatment. The patient after treatment has a high risk of developing opportunistic infections, which are typical for his pathogen, which, however, is unusual for the resuscitator.

When treating and examining it is desirable to attract at the first stage a specialist who has experience in the treatment of opportunistic infections.