Infectious complications in cancer patients

Infectious complications are the most common reasons for admission of cancer patients to the intensive care unit. Both the tumor itself and its treatment (chemotherapy, radiation therapy, surgery) change the spectrum of prevailing pathogens (opportunistic, atypical pathogens), the clinical picture of common infections (absence or change of usual symptoms), the severity of the infectious process (fulminant sepsis), etc. The article describes the main differences in the diagnosis and treatment of infections in cancer patients. It is optimal to involve the specialist who carried out the antitumor treatment in differential diagnostics.

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Special clinical situations

Bacteremia

The risk of developing bacteremia in patients with cancer directly depends on the presence and duration of neutropenia. Detection of bacteremia in most cases is a reason for modifying the initial therapy. Detection of coagulase-negative staphylococci and corynebacteria in blood cultures is often due to contamination. However, in immunosuppressed patients (especially in patients with central venous catheters), these skin saprophytes can cause bacteremia. When coagulase-negative staphylococci are cultured 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 repeat study 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 growth of the pathogen even from a single blood sample requires the addition of vancomycin to the initial antibiotic therapy.

If a gram-negative pathogen is detected, the decision is made depending on the clinical situation. If the pathogen is isolated from a blood sample obtained before the start of empirical antibacterial therapy, the initial therapy regimen is used until data on the sensitivity of the pathogen is obtained for as long as the patient's condition remains clinically stable. If it worsens or the gram-negative pathogen is isolated from the blood while empirical antibacterial therapy is underway, an immediate change in antibiotic therapy is necessary.

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Patients with vascular catheters

Most catheter-site infections are cured without catheter removal by antibiotics. Vancomycin is the drug of choice until antibiotic susceptibility data are available. In tunnel infections, in addition to antibiotics, catheter removal is also required. Catheter-associated bacteremia is treated with antibiotics; removal of non-implantable catheters in clinically stable patients is left to the discretion of the physician. Implantable catheters may be left in place while antibiotics are administered and blood cultures are performed daily. Removal is indicated if bacteremia persists for more than three days or if bacteremia due to the same pathogen recurs. Catheters should also be removed from all patients with signs of septic shock if highly 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 case of sinusitis in a patient with neutropenia, it is necessary to prescribe first-line drugs for the treatment of neutropenic infection. If there is no improvement within 3 days, therapeutic and diagnostic aspiration of the sinus contents is recommended. If fungal pathogens are detected, therapy is carried out with high doses of amphotericin B at 1-1.5 mg / (kg x day). If aspiration is not possible, therapy is prescribed empirically. Surgical sanitation is necessary, since against the background of neutropenia, drug therapy alone rarely leads to a cure.

Pulmonary infiltrates

Pulmonary infiltrates in immunosuppressed patients are classified as early focal, refractory focal, late focal, and interstitial diffuse.

Early focal infiltrates. Early infiltrates are those that appear during the first episode of neutropenic fever. The infection is most often caused by bacterial pathogens such as Enterobactenaceae, Staphylococcus aureus. When foci appear, at least two cultures of blood, urine and sputum should be performed.

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

Late focal infiltrates occur on or after the seventh day of empirical therapy in patients with persistent neutropenia. The most common pathogen causing late infiltrates in the setting of persistent neutropenia is Aspergillus. As in refractory pneumonia, late infiltrates are caused by infection (or superinfection) with bacteria, viruses, and protozoa that are resistant to the initial regimen.

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

Neutropenic enterocolitis

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

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

Surgical treatment is currently indicated only for a small group of patients:

• Continued gastrointestinal bleeding after resolution of neutropenia, thrombocytopenia and correction of the coagulation system.
• The presence of signs of intestinal perforation 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).

In a relatively stable patient, it is recommended to postpone surgical treatment until neutropenia resolves, even in cases of limited localized peritonitis, pericecal effusion, or suspected occluded perforation. If necessary, surgical intervention includes resection of necrotic bowel (most often right hemicolectomy) or decompressive ileostomy.

Anorectal infections

Anorectal infections in patients with malignant neoplasms are life-threatening. In patients receiving intensive chemotherapy (the main risk factor), severe anorectal infections are observed in approximately 5% of cases.

In this regard, it is necessary to conduct consistent examinations of the anorectal area. The presence of large foci of softening, maceration of the skin is a reason for immediate prescription of therapy with mandatory antianaerobic activity (ceftazidime + metronidazole or monotherapy with carbapenems). Digital rectal examination of patients is not performed, since it carries an additional risk of spreading infection and bleeding. CT examination is useful if there is a suspicion of spread of infection to pelvic structures. Indications for surgical treatment are progression of infection despite adequate antibiotic therapy, obvious tissue necrosis or the appearance of fluctuation.

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Diagnostics

History is used to quickly identify risk factors for developing a specific infection. The presence of infectious complications during previous courses of similar therapy predicts the risk of their development during a given hospitalization. For example, a history of clostridial colitis should prompt additional testing (stool test for Clostridium difficile toxin) in the event of fever and diarrhea. Previous invasive candidiasis or aspergillosis may predict recurrence of infection during the next period of neutropenia.

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Physical examination

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

Laboratory research

The necessary diagnostic minimum, regardless of tests performed for other indications:

• complete blood count with white blood cell count,
• biochemical blood test (glucose and total protein, bilirubin and creatinine, urea, liver enzymes),
• urine culture before prescribing antibacterial therapy,
• blood culture before prescribing antibacterial therapy (blood samples must be taken from at least two points from each lumen of the CBC, if present, and from a peripheral vein),
• sowing of pathological exudates (sputum, pus) and material from potentially infected foci (aspirate from the area of subcutaneous cellulitis).

Instrumental research

Chest X-ray. In the presence of symptoms of lung damage, CT is preferable, as it can detect pneumonia in 50% of patients who have no changes in standard X-ray.

Ultrasound of abdominal organs in the presence of complaints and anamnesis data (diarrhea, abdominal pain).

Features of diagnosis and treatment of infection in various clinical situations

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Patients without severe neutropenia

In patients without severe neutropenia (neutrophils>0.5x10 ⁹ /l) who do not receive conservative antitumor and cytostatic therapy:

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

Patients with neutropenia

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

• <1.0x10 ⁹ /l - increased,
• <0.5x10 ⁹ /l - high,
• <0.1U10 ⁹ /l - extremely high.

The most dangerous is neutropenia <0.1x10 ⁹ /l lasting more than 10 days. The patient experiences more severe infectious complications, accelerated dissemination of the pathogen (bacteremia, fungemia are encountered 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. Infection agents are most 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, blurred by the absence of cough, sputum and radiographic changes in pneumonia, the absence of pyuria in urinary infections and pleocytosis in meningitis, massive phlegmons without pronounced induration and redness, etc. The only symptom of infection that is observed as often as in patients without neutropenia is fever. In this regard, in neutropenia, febrile fever is a sufficient basis for prescribing antibiotics.

In febrile neutropenia, the neutrophil level is <0.5x10 ⁹ /l or <1.0x10 ⁹ /l with a tendency to rapidly decrease. The treatment and examination tactics are closely related to the features described above (see anamnesis, physical examination, laboratory / instrumental examination).

Treatment of infection against the background of neutropenia requires mandatory administration of broad-spectrum antibacterial drugs that have a bactericidal effect on the most dangerous pathogens. Afebrile patients with neutropenia who have signs or symptoms similar to those of infection also receive antibacterial therapy.

Main differences in treatment tactics in the presence and absence of neutropenia

Evidence of infection	Without neutropenia	With neutropenia
Bacteriologically documented (pathogen identified)	Antibiotic therapy according to the pathogen sensitivity spectrum	Broad-spectrum antibiotics with mandatory activity against Pseudomonas acidovorans + antibiotic therapy directed at resistant pathogen
Clinically documented (focus of infection identified)	Antibiotic therapy directed at the most likely pathogen	Broad-spectrum antibiotics with mandatory activity against Pseudomonas acidovorans +/- antibiotic therapy directed at the most likely resistant pathogen
Fever of unknown origin (the source and pathogen are not identified)	Prescribing antibiotic therapy only with clinical or bacteriological confirmation of infection or in the extremely serious condition of the patient	Empirical broad-spectrum antibiotic therapy with mandatory activity against Pseudomonas acidovorans

In case of an infectious process caused by resistant gram-negative flora, a combination of the basic drug with an aminoglycoside (amikacin 15 mg/kg once a day intravenously) is possible. In case of severe damage to the mucous membrane or suspected catheter sepsis, vancomycin is prescribed at 1 g twice a day intravenously. Further modification of antibacterial therapy is desirable to be carried out in cooperation with the specialist who carried out the antitumor treatment.

Algorithm of actions in the most frequently encountered clinical situations

Clinical situation	Examination and treatment
Neutropenic fever persisting despite broad-spectrum antibiotic therapy (3-7 days) without an identified infectious focus	Re-examination Addition of empirical antifungal therapy (amphotericin B 0.5-0.6 mg/kg per day or fluconazole 400 mg per day) If fluconazole was used previously, it must be replaced with amphotericin B
Return of fever after 14 or more days of initially effective therapy (without an identified source of infection)	Highly suspicious for fungal infection Prescribe empirical therapy with amphotericin B at 0.5-0.6 mg/kg per day Perform CT If a mold infection is suspected, BAL and biopsy are prescribed If the diagnosis is confirmed, amphotericin B in high doses (1.0-1.5 mg/kg per day)
Persistent or recurrent fever without an identified focus against the background of recovery of the neutrophil level	Possible hepatosplenic candidiasis. Conduct ultrasound and/or CT of the abdominal organs. If foci are detected, percutaneous needle biopsy with bacteriological examination is indicated.
Gram-positive microorganism in blood obtained before initiation of empirical antibiotic therapy	Add Vancomycin
Gram-negative microorganism in blood obtained before initiation of empirical antibiotic therapy	If the patient's condition is stable, it is necessary to continue the initial antibiotic therapy; in case of clinical instability, it is necessary to replace ceftazidime (if used initially) with carbapenems and add an aminoglycoside. Modification of the regimen according to the spectrum of pathogen sensitivity should be carried out after receiving data from the bacteriological laboratory.
Gram-positive microorganism in blood obtained during empirical antibiotic therapy	Add Vancomycin
Gram-negative microorganism in blood obtained during empirical antibiotic therapy	Suspect a resistant pathogen (depending on the antibiotic regimen used) If ceftazidime was initially used, replace with carbapenems and add an aminoglycoside If carbapenems were used initially, then the most likely pathogen may be Pseudomonas Ciprofloxacin and trimethoprim should be prescribed Further modification of therapy is carried out based on susceptibility data
Necrotic gingivitis	If ceftazidime or cefepime were used in the initial therapy, there is a high probability of anaerobic pathogens . Replacement with carbapenems or addition of metronidazole is necessary to affect the potential anaerobic pathogen.
Signs of sinusitis	Sinus drainage for diagnostic and therapeutic purposes Gram-negative infection (Enterobacteriaceae or Pseudomonas) is likely, with neutropenia >10 days, mold infection is more likely
New pulmonary infiltrates after resolution of neutropenia	There may be a "manifestation" of an inflammatory response to old infectious foci. If the patient has no symptoms - observation, if there are symptoms - BAL and biopsy to identify the pathogen
Diffuse infiltrates	If the patient is receiving glucocorticoids - suspected pneumonia caused by Pneumocystis carinii Possible infections caused by respiratory viruses, bacterial pneumonia and non-infectious causes (hemorrhages, ARDS, toxicity of chemotherapy drugs and radiation) It is highly desirable to perform BAL urgently
Acute abdominal pain	Differential diagnosis includes diseases observed outside the period of neutropenia (cholecystitis, appendicitis, etc.) and neutropenic enterocolitis . Antibiotic therapy is required to cover the intestinal flora and anaerobic pathogens (ceftazidime or cefepime + metronidazole, or imipenem monotherapy). If necessary, surgical intervention.
Perirectal infection	Antibiotic therapy is required to cover intestinal flora and anaerobic pathogens (ceftazidime or cefepime + metronidazole, or imipenem monotherapy) If necessary - surgical intervention
Cellulitis in the area of catheter insertion	Most likely gram-positive pathogens - inhabitants of the skin (possibly resistant) Vancomycin must be added
Infection along the catheter (tunnelitis)	Most likely gram-positive pathogens - inhabitants of the skin (possibly resistant) Removal of the catheter and addition of vancomycin are necessary
Suppuration (discharge) around the catheter	Clean the edges, remove the exudate Send the exudate for bacteriological examination If necessary - remove the catheter and antibiotic therapy
Local catheter infection caused by Aspergillus or Mycobacterium	Removal of the catheter, local treatment Excision of tissue around the subcutaneous tunnel may be necessary Anti-infective therapy depending on the pathogen
Catheter-associated bacteremia	Add the necessary antibiotic Remove the catheter if a highly resistant pathogen (Mycobacterium, Candida albicans) is detected Removal is also indicated in case of resistance to antibacterial therapy and/or hemodynamic instability
New foci of infiltration during neutropenia	Possible resistant bacteria or mold fungi If BAL material or sputum is not informative - empirical therapy with amphotericin B in high doses (1-1.5 mg/kg per day)

Patients with damage to mucous membranes

Patients with mucosal damage have a low degree of immunosuppression, the development of concomitant neutropenia is possible, the severity of infectious complications is increased, since the damaged mucosa is a large "wound surface" that comes into contact with highly pathogenic microorganisms and the environment (oral secretions, feces, etc.). The spectrum of pathogens depends on the area of damage; in case of damage to the oral mucosa, predominantly gram-positive pathogens are detected, in case of damage to the intestinal mucosa - gram-negative and anaerobic pathogens.

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

The tactics of treatment and examination are related to the features 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 intensive care unit, it is justified to add vancomycin to the first-line antibacterial therapy. In the development of a severe systemic infection against the background of severe damage to the intestinal mucosa, the most aggressive antibacterial therapy is prescribed: carbapenems + aminoglycosides + vancomycin +/- antifungal drug.

Patients receiving glucocorticoids

Patients receiving glucocorticoids have a high degree of immunosuppression, and infectious complications are particularly severe. With long-term use of drugs, even in relatively small doses (8-16 mg dexamethasone per day), the likelihood of developing infectious complications increases significantly. The causative agents of infection are most often yeast and mold fungi.

It is possible that a habitual infectious process may have few symptoms; the doctor must be alert in terms of diagnosing “unusual” infections.

The tactics of treatment and examination are closely related to the features 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 involve a consultant with experience in treating patients with atypical infections (hematologist, infectious disease specialist).

Patients after splenectomy

Splenectomized patients have a high degree of immunosuppression against encapsulated bacteria, and prophylactic use of penicillins increases the risk of the presence of resistant pathogens.

After splenectomy, infections caused by encapsulated pathogens are unusually severe and rapidly fatal.

The tactics of examining patients is usual, it is desirable to obtain data on the prophylactic use of penicillins. Preparations that are active against encapsulated bacteria are prescribed without fail: cephalosporins, macrolides, trimethoprim + sulfamethoxazole. Penicillins are used only in the absence of prophylactic therapy.

Patients after transplantation and chemotherapy

Patients who have undergone chemotherapy (fludarabine, cladribine, alemtuzumab) and allogeneic bone marrow transplantation have an extremely high degree of immunosuppression, especially in relation to cellular immunity, which persists for months and years after the treatment. After treatment, the patient has a high risk of developing opportunistic infections that are typical for their pathogen, which, however, is unusual for a resuscitator.

During treatment and examination, it is advisable to involve a specialist who has experience in treating opportunistic infections at the very first stage.