Febrile Neutropenia - Definition and Causes

 

               Chemotherapy-induced neutropenia remains the major predisposing factor to infection in cancer patients. The risk of infection correlates with the degree of severity and the duration of neutropenia. Because of the decreased inflammatory response during neutropenia, the symptoms and signs of infection are attenuated or even absent and very often, fever is the only early manifestation. This fact justifies the term of febrile neutropenia generally used in this specific situation. Febrile neutropenia is associated with significant morbidity and results in delays in chemotherapy schedules or in reductions of chemotherapy dose-intensity, which may compromise the outcome. The overall mortality rate of febrile neutropenia is approximately 9.5 % in solid tumors and 14 % in lymphoma and leukemia, and the infection-related mortality rates are 2.3 % and 5 % respectively.

               There is also an increase of costs associated with the management of febrile neutropenia in terms of hospitalization, antibiotic treatment and other supportive measures.

 

Definitions

               Neutropenia refers to an absolute neutrophil count less than 500 cells/l. Short duration of neutropenia (< 7 days) is usually seen in patients with solid tumor or lymphoma receiving standard chemotherapy regimen while a long duration of neutropenia (> 7 days) is reported in patients receiving intensive chemotherapy with autologous HSCT rescue (~ 10 days of neutropenia), in patients with allogeneic HSCT and in patients with induction therapy for acute leukemia (> 21 days of neutropenia).

               Fever is defined as one peak of axillary temperature above 38.3C (101F) or two peaks above 38C (100F) within 24 hours and separated by at least 2 hours. Clinically documented infection refers to episodes where a site of infection has been identified either clinically or radiologically.

               Microbiologically documented infection refers to episodes where a pathogen has been identified in microbiological samples. Fever of unknown origin indicates episodes of fever where an infection cannot be demonstrated neither clinically nor microbiologically and in whom a non-infectious cause of fever has also been excluded. It is important to stress that the majority of the patients with fever of unknown origin during neutropenia still respond to empiric broad-spectrum antibiotics in the same proportion as patients with documented infections.

    Risk Assessment of Chemotherapy-Induced Neutropenia and Its Complications

The occurrence of a febrile neutropenic episode results from the conjunction of several conditions, among which the intensity of the chemotherapy plays a major role in addition to the type and stage of the tumor and to several predisposing factors that are specific to each patient. The risk of febrile neutropenia is highest among patients receiving chemotherapy for acute leukemia or undergoing hematopoietic stem cell transplantation, exceeding 85% of cases. For patients with lymphoma or solid tumor, this risk is much lower although highly variable and more difficult to predict. The type of chemotherapy agents, dosage and number of drugs given in combination markedly influence the rate of febrile neutropenia. For many common regimens of chemotherapy, categorization lists are available, based on mean percentage of febrile neutropenia reported in clinical trials (NCCN, ASCO, EORTC). Paclitaxel, docetaxel, irinotecan, topotecan and high-dose cyclophosphamide, anthracycline, cisplatin, ifosfamide, etoposide, cytarabine have all been identified as significant predictors for febrile neutropenia. The combination of more than 2 myelosuppressive agents and a planned delivery higher than 85 % have been reported in a prospective cohort study, as risk factors for febrile neutropenia and validated subsequently in a randomly selected sample. Several patient-specific factors were found to be significant predictors of febrile neutropenia occurrence in multivariate risk-model studies. These include advanced age, poor performance and nutritional status, the presence of co-morbid conditions such as renal, liver or heart insufficiency and diabetes, pre-treatment low blood cell counts and other laboratory abnormalities like serum albumin concentration below 3.5 g/dl or high LDH values. A body temperature higher than 40C at presentation, hypotension or shock, hematological malignancy, pneumonia and infection at intravenous site, are all significant predictors of bacteremia. Once a febrile neutropenic episode has occurred, the determination of the MASCC (Multinational Association of Supportive Care in Cancer) risk-index score which integrates several clinical parameters that can be readily assessed at the bed-side is a good risk predictor of complications including death.

    Sites of Involvement and Pathogens

The major sites of infection during neutropenia and the most common offending pathogens are summarized in Table 1. The alimentary tract including oral cavity, esophagus, colon and rectum is the most common source of infection in neutropenic patients. Breaches in mucosal barriers accompanying intense chemotherapeutic regimens, allow members of the indigenous flora to enter the bloodstream. Oral mucositis is the portal of entry of viridans streptococci bacteremia with S. mitis and S. sanguis being the most common isolated species. Potentially lethal complications such as shock and acute respiratory distress syndrome have been associated with viridans streptococcal primary bacteremia in 11 % of cases.

Fusobacterium bacteremia, mainly due to F. nucleatum and less frequently to F. necrophorum, is another complication associated with oral mucositis during neutropenia. Despite the well established virulence of this anaerobic gram-negative bacilli, most of the reported cases in neutropenic patients have a favorable outcomes. Stomatococcus mucilaginosus, another inhabitant of the oral cavity, has been reported since the 1990s mainly in primary bacteremias. However, in the pediatric population cases of meningitis have been described. Our experience in 8 neutropenic adult patients with bacteremia due to Stomatococcus mucilaginosus was that of manifestations of sepsis without central nervous system involvement and all patients survived. Other commensals of the mouth flora less frequently reported include Leptotrichia buccalis, Capnocytophaga spp., Eikenella corrodens, Rothia dentocariosa, Eubacterium spp. and Prevotella buccae. Necrotizing gingivitis is associated with Bacteroides species and esophagitis is mainly due to Candida spp. or Herpes simplex virus.

Neutropenic enterocolitis (or typhlitis) is an extreme form of mucosal barrier injury induced by chemotherapy through the generation of reactive oxygen radicals and causing damage to the cells, tissues and blood vessels of the intestine. The ileo-cecal region is the most frequently involved with longitudinal extension to the ascending colon or small bowel. Hemorrhagic necrosis, ulcerations with bacterial colonization, transmural inflammation and marked thickening of the bowel wall are the main pathological findings. The clinical manifestations include fever, abdominal pain, diarrhea, right lower quadrant pain and abdominal distension. Historically, typhlitis has been associated with Clostridium septicum bacteremia but recent series, reported concomitant bacteremia with enterococci, streptococci, enterobacteriacae, P. aeruginosa and Candida spp. Rare cases due to Aspergillus spp. or zygomycetes have been discovered on histopathology examination and deep-seated tissue cultures. Bowel wall thickening more than 4 mm and over more than 30 mm, demonstrated either by ultrasound or computed tomography is suggestive of neutropenic enterocolitis.

Circumferential wall thickening of cecum with inflammation of pericolonic fat tissue consistent with neutropenic enterocolitis.

Perirectal abscess is usually of polymicrobial origin involving anaerobes, predominantly Bacteroides fragilis, which are associated with facultatively anaerobic Gram-negative bacteria and Gram-positive cocci. Pain on defecation may be the only manifestation in neutropenic patients.

The respiratory tract, mainly sinuses and lungs, is a common site of infection during neutropenia. During a short period of neutropenia (< 7 days), pneumonia and sinusitis are usually caused by common respiratory pathogens such as Streptococcus pneumoniae, and Haemophilus influenzae and less frequently by Enterobacteriacae and P. aeruginosa. While for long durations of neutropenia (> 10 days), the risk of having a respiratory infection caused by nosocomial multidrug resistant bacteria or by a filamentous fungi increases substantially. Aspergillus spp. and zygomycetes occur predominantly in acute leukemia, myelodysplastic syndrome and allogeneic hematopoietic stem cell transplant patients. The symptoms and signs of pneumonia may be lacking in neutropenic patients, and the chest CT scan is superior to the standard X-ray in showing the presence, the type and exact topography of a pulmonary infiltrate.

The skin including the catheter-site can be a major source of severe infections during neutropenia. Catheter-site cellulitis and tunnelitis (a) are caused by S. aureus, coagulase-negative Staphylococcus (CNS), Bacillus spp., Corynebacterium jeikeium, Candida spp., Fusarium spp., Hansenula anomala, Rhodotorula and Malassezia furfur in case of total parenteral nutrition. Furonculosis (b) due to S. aureus and perionyxis (c) due to S. aureus or fungi are important clues for adequate management. Moisture-laden areas of the skin such as the scrotum, the inguinal, axillary and perineal regions and the skin around the nares, are the predilection sites of primary echtyma gangrenosum (d), a severe necrotizing cellulitis most often induced by P. aeruginosa.

Finally, secondary skin lesions may be the only manifestation of many disseminated infections (e).

a)Cellulitis and tunnelitis at catheter site due to S. aureus b)Necrotic bullous lesions of the skin due to S. aureus c)Ungueal and toe infection due to disseminated Fusarium during a febrile neutropenic episode.

Ungueal and toe infection due to disseminated Fusarium during a febrile neutropenic episode 60 year old malnourished female burn patient with Pseudomonas bacteremia and biopsy confirmed ecthyma gangrenosum

Exposed prosthetic joint after wound dehiscence in a severely malnourished patient Small red popular skin lesions in a neutropenic patient with disseminated candidiasis.

In a prospective trial which addressed extensively the causes of fever in 116 consecutive neutropenic episodes we found that 70% were due to documented infections either clinically only in 24%, or microbiologically only in 22% or both clinically and microbiologically in 24%. Bacteremia represented 32% with primary bacteremia in 18% and secondary bacteremia in 14 %. Fever of unknown origin occurred in 17% of episodes while 13% were of non-infectious origin (Figure 1). Head and neck sites of infection were the most prevalent representing 21% and include oral mucositis grade 3 or 4, pharyngitis and sinusitis. Lower respiratory tract of infections accounted for 15%. Gastrointestinal and urinary tract infections represented 7.5% each, skin and soft tissue infections 6.3% and central nervous system infections were rare representing only 2.5%. Septic shock was present in 6.3% of all episodes.  

Table 1: Sites of Involvement and Common Pathogens    

  Primary Bacteremia

      Viridans Streptococci

      Enterobacteriacae : E. coli, Klebsiella spp.

      Pseudomonas aeruginosa

      Candida spp.

 

  Pneumonia or Sinusitis

      Conventional bacteria (frequent concomitant bacteremia)

      Aspergillus spp.

      Zygomycetes spp.

      Fusarium spp.

 

  Skin and Soft Tissue (Including Catheter Site)

       Coagulase negative staphylococci

       Staphylococcus aureus

       Bacillus spp.

       Corynebacterium jeikeium

       Pseudomonas aeruginosa (ecthyma gangrenosum)

       Candida spp., Trichosporon spp., Malassezia furfur

 

  Oral Mucositis

       HSV

       Oral bacterial flora (viridans Streptococci, Fusabacterium spp, Prevotella,

                          Stomatococcus spp., Eikenella corrodens, Leptotrichia, )

       Bacteroides spp. (necrotizing gingivitis)

 

  Perianal Abcess

       Polymicrobial (Gram-positive cocci, Gram-negative bacilli and anaerobes)

 

  Typhlitis

       Clostridium septicum

       Other Clostridia

       Enterobacteriacae

       Bacteroides fragilis

       Candida spp.

Figure 1:  Causes of Fever During Neutropenia