OVERVIEW: What every practitioner needs to know

Are you sure your patient has an infection and is a recipient of a hematopoietic cell transplant? What should you expect to find?

  • Neutropenic fever symptoms: Fever is often the only finding. Rigors may be present. Hypotension is infrequently present and is a sign of more serious infection and sepsis. There may be localizing findings such as oral pain or pleuritic pain (suggestive of pneumonia), diarrhea or abdominal pain (suggestive of typhlitis or C. difficile colitis), skin lesions (suggestive of infectious emboli), pain or eythema over indwelling venous catheter (suggestive of soft tissue infection, dysuria (suggestive of urinary tract infection [UTI]).

  • Non-neutropenic fever physical findings: same as with neutropenic fever, except findings more prominent because patient can manifest an inflammatory response.

  • Pneumonia symptoms: fever, cough, sputum, pleuritic pain

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  • Pneumonia findings: rales, rhonchi, pleural rub

  • Diarrhea symptoms: diarrhea, perianal pain, abdominal cramps

  • Diarrhea findings, loose stools, perianal cutaneous breakdown

  • Rash symptoms: vesicles, erythema, painful nodules

  • Rash findings: echthyma, vesicles, maculopapular erythematous lesions, cutaneous or subcutaneous nodules

How did the hematopoietic cell transplant recipient develop an infection? What was the primary source from which the infection spread?

  • Neutropenic fever: This occurs primarily during the first 3-4 weeks after transplant during the “pre-engraftment” period. Neutropenia less commonly occurs later as a result of multiple factors, including myelosuppression from various drugs, viral infections, secondary graft failure, or relapse. Neutrophils are key defenses against bacteria. Mucosal injury from chemoradiotherapy allows easier entry of commensal gut bacteria and fungi into bloodstream. Implanted central venous catheters breech the cutaneous barriers and allow colonizing bacteria and fungi entry into the bloodstream. In many instances, no pathogen can be identified early after the onset of neutropenic fever. Prior studies demonstrated that waiting eventually results in demonstration of a pathogen in most patients, and is associated with a high rate of morbidity and mortality.

  • Neutropenic fever epidemiology: Bacteremia is the most common infection, but blood cultures are positive in only about 20% of episodes. The majority of bloodstream isolates are Gram positive bacteria, mostly Staphylococcus epidermidis and much less commonly viridans streptococci and Staphylococcus aureus. With the exception of S. aureus, the Gram positive organisms are generally less virulent. In contrast, the less common Gram negative organisms are highly virulent and are the principal targets of empiric treatment regimens. The most common Gram negative pathogens are Escherichia coli, Klebsiella spp, Enterobacter spp., and Pseudomonas aeruginosa, and less commonly Citrobacter spp, Acinetobacter spp, and Stenotrophomonas maltophilia. When neutropenia is prolonged, Candida spp increasingly cause fungemia. Aspergillus can be a cause of pneumonia if neutropenia persists beyond 14 days.

  • Non-neutropenic fever: This occurs at neutrophil recovery as the so-called engraftment syndrome which is a non-infectious syndrome, presumably caused by inflammatory cytokines. Infection needs to be excluded quickly, and corticosteroids are the preferred treatment, not antibiotics. Central venous catheters typically remain in place for long periods, and catheter-associated bloodstream infections are common causes of non-neutropenic fevers. The profound deficits in B and T cell immunity make patients vulnerable for viral and fungal infections. Graft versus host disease (GVHD) necessitates use of corticosteroids and other T cell immunosuppressive therapies that prolong the T cell deficiency. T and B cell immunity gradually recover over the 6-12 months after transplant. This occurs more quickly after autologous transplantation; after allogeneic transplantation, the occurrence of GVHD slows recovery, and persistent B and T cell immunodeficiency can be present for years.

  • Non-neutropenic fever epidemiology: Non-infectious causes have been mentioned due to engraftment syndrome or occasionally related to drugs. Catheter-associated infections frequently are due to Gram positive bacteria, especially S. epidermidis, but other Gram positive and Gram negative bacteria and occasionally Candida also cause catheter infections. Other causes of fever include cytomegalovirus viremia, especially after allogeneic transplantation, candidiasis, and aspergillosis. Aspergillus is particularly problematic if the patient experiences GVHD. In patients with chronic GVHD, severe infections due to encapsulated bacteria can occur.

  • Pneumonia epidemiology: Pneumonias can be divided into diffuse and nodular patterns based on their radiologic appearance on computed tomographic (CT) scan and may have non-infectious and infectious causes.

    Diffuse: approximately half are non-infectious and half are infectious. Non-infectious causes include hemorrhage, pulmonary edema, cryptogenic organizing pneumonia, and drug or radiation toxicity. Infectious causes include cytomegalovirus, Pneumocystis jiroveci, respiratory viruses, and Legionella.

    Nodular: Most of these are infectious. Bacteria and fungi are common causes of pneumonia after transplant. The bacterial pathogens are a broad mix of Gram positive and Gram negative pathogens in roughly similar proportions. Approximately 40-50% of pneumonias are due to molds. Aspergillus is by far the most common pathogen in this group, accounting for 70-80% of mold infections after transplantation. About 20% are due to Mucorales, Scedosporium, and Fusarium. Late after transplant, Nocardia is an occasional cause of nodular pneumonia

  • Diarrhea: Mucosal injury from chemoradiotherapy, along with neutropenia, contributes to typhlitis. Use of antibiotics and the use of drugs to suppress acid contribute to C. difficile disease.

  • Diarrhea epidemiology: Rarely are pathogens identified in typhlitis. Pathological studies suggest typhlitis to be due to principally Gram negative bacteria, with possible contributions from anaerobic bacteria, Candida, and possibly staphylococci.

  • Rash epidemiology: Rashes are common after transplantation, present with many different appearances, and can be due to non-infectious and infectious etiologies. GVHD is the most concerning. Drug reactions are also common. Infectious causes include varicella-zoster with the typical vesicular appearance although infrequently, nodules with central ulcerations can occur. The onset of zoster is typically 4-9 months after transplant but can occasionally occur earlier and more often can occur later. Although the dermatomal distribution is characteristic, dissemination can occur especially in those on intensive immunosuppression. Cutaneous and subcutaneous nodules result with transplantation, but can occasionally appear earlier and frequently occur much later. Dermatomal distribution is characteristic, but dissemination can occur in those on intensive immunosuppression. Cutaneous and subcutaneous nodules with ischemic centers and surrounding inflammation are often signs of disseminated fungal and bacterial infections.

Which recipients of hematopoietic cell transplantation are at greater risk of developing an infection?

  • Neutropenia: neutropenic fever and typhlitis

  • Antibiotic use: C. difficile, antibiotic resistant bacteria

  • Implanted venous catheters: bacteria and Candida

  • Intensive transplant conditioning regiments: neutropenic infections

  • Graft versus host disease: Mold infections, encapsulated bacteria (with chronic GVHD), zoster, Nocardia

  • Cord blood as stem cell source: EBV and HHV6 infections

  • T cell depletion of stem cell graft: fungal and herpes viral infections

  • Use of anti-thymocyte globulin: EBV and HHV6 infections

  • Use of methotrexate as GVHD prophylaxis: neutropenic infections

  • CMV seropositivity before transplant: CMV infection

  • CMV viremia: subsequent CMV pneumonia

  • VZV seropositivity before transplant: zoster

Beware: there are other diseases that can mimic infection in recipients of hematopoietic cell transplantation:

  • Neutropenic fever: drug reactions

  • Non-neutropenic fever: drug reaction, engraftment syndrome, GVHD

  • Pneumonia:

    Diffuse: hemorrhage, pulmonary edema, cryptogenic organizing pneumonia, chemotherapy or radiotherapy toxicity

    Nodular: rarely chemotherapy toxicity

  • Diarrhea: chemotherapy or other drugs

  • Rash: GVHD, multiple drugs.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Neutropenic fever: blood cultures (positive in only 20%); cultures or biopsy of any site of suspected infection, If respiratory infection suspected, chest CT; if GU infection suspected, urine culture; if diarrhea, C. difficile toxin assay, and if negative parasite, screen and viral studies.

  • Non-neutropenic fever: blood cultures, plasma CMV PCR or pp65 antigen test, serum Aspergillus galactomannan assay (for suspected Aspergillus pneumonia). Peripheral WBC with differential.

  • Pneumonia: CT scan; nasal and/or throat swab for respiratory viral PCR and cultures. Plasma CMV PCR or antigen assay, bronchoscopy with BAL for CMV, respiratory viruses, including adenovirus, Pneumocystis PCR or cytology, BAL Aspergillus galactomannan (less likely as cause of diffuse infiltrates), BAL cultures for bacteria, mycobacteria, and fungi, transbronchial biopsy (only if non-neutropenic and adequate respiratory reserve due to risk for pneumothorax and hemorrhage); urine for Legionella antigen; mycobacterial blood cultures.

  • Diarrhea: stool for C. difficile toxin assay, parasite screen, adenovirus, and enteric viruses; if persistent then colonoscopy with biopsy for histopathology (for GVHD) and CMV-specific immunofluorescent stain.

  • Rash: if vesicles present, do scraping for VZV and HSV DFA and viral culture; for nodules, biopsy for histopathology, fungal stains and bacterial and fungal cultures.

Results that confirm the diagnosis

  • Blood cultures document bloodstream infections.

  • Positive plasma CMV PCR documents CMV viremia. This may be positive in asymptomatic as well as symptomatic patients. Viremia is a risk factor for subsequent CMV pneumonia

  • Immunofluorescent stain or PCR for PCP; indicates PCP pneumonia

  • BAL stain for CMV: indicates CMV pneumonia

  • BAL PCR for respiratory virus: indicates presence of virus and infection if pulmonary infiltrate present; does not differentiate upper from lower tract infection.

  • Serum or BAL Aspergillus galactomannan: documents invasive Aspergillosis (if clinical picture compatible)

  • Stool C difficile toxin positive: indicates C difficile infection

What imaging studies will be helpful in making or excluding the diagnosis of infection in recipients of hematopoietic cell transplantation?

  • CT scan of chest: most important initial test for pneumonia; divides pneumonias into diffuse and nodular. $$$

  • CT scan of sinuses: helpful to detect sinusitis; if bony erosion present strongly suggestive of fungal etiology rather than bacterial. $$

  • CT scan of abdomen: important in assessment of diarrhea or abdominal pain; diagnostic features of typhlitis (bowel wall thickening, especially in cecum. $$$

($ = 60-125, $$ 125-500, $$$ 500-1,000, $$$$ > 1,000)

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has an infection, what therapies should you initiate immediately?

  • Neutropenic fever: prompt history and physical exam focusing on infections, perform blood cultures, and initiate empiric antibiotic therapy to cover Gram negative bacteria.

  • Non-neutropenic fever, at time of engraftment, identify any sites of suspected infections from history and exam, perform blood cultures; if no infections identified within 24 hours, initiate corticosteroids for presumptive engraftment syndrome (start steroids immediately if respiratory compromise while evaluating for infection). If CMV viremia demonstrated, initiate pre-emptive antiviral therapy.

  • Pneumonia: CT scan and consult Pulmonary Service for bronchoscopy. If diffuse and bronchoscopy is done promptly, await results of testing; if patient severely ill, coverage for PCP, CMV and respiratory viruses is acceptable until results known. If nodular infiltrates, bacteria and molds most likely. While evaluation is proceeding, initiate antibiotics to cover Gram positive and Gram negative bacteria and antifungals to cover Aspergillus. If sinus infection noted, mucormycosis is more likely and antifungal agent should cover mucormycosis as well as other molds.

  • Diarrhea: if neutropenic, get CT scan and if typhlitis seen, use broad antimicrobial coverage for Gram negative bacteria, Candida, and anaerobes. If non-neutropenic and if C difficile toxin assay positive, treat with metronidazole; if negative perform colonoscopy and respond to diagnostic results.

  • Rash: if vesicular, initiate acyclovir; if nodular, get biopsy results to determine etiology and act once results known.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection, what anti-infective should I order?

Neutropenic fever: Prompt initiation of empiric antibiotics is key. Coverage against virulent Gram negative organisms is the foundation of empiric therapy. Several regimens are acceptable (See Table I)

Table I.
Syndrome Antibiotic Dose Alternative
Neutropenic fever Piperacillin/tazobactamImipenemMeropenemCefepimeCeftazidime (less acceptable due to growing resistance) 4.5 g Q8H500 mg Q6H1 gm Q8H2 gm Q8H2 gm Q8H For penicillin allergy, most patients tolerated cephalosporins, however if history of urticaria, lip swelling or bronchospasm, alternative regimens should be considered such as aztreonam or ciprofloxacin plus vancomycin
Non-neutropenic fever Treat specific pathogen identified on assessment
Bacterial Pneumonia combination of vancomycin +cefepime (Once specific pathogen known tailor therapy appropriately) 1 gm Q12H2 gm Q12H (or Q8H if neutropenic) azithromycin plus levofloxacin
Aspergillus pneumonia Voriconazole 6 gm/kg Q12H x 2 dose, then 4 gm Q12H thereafter; once stable can change to oral 200 mg BID Lipid formulation amphotericin B 3-5 mg/kg/day
PCP pneumonia sulfamethoxazole-trimethoprim 15-20 mg/kg/d in 3-4 divided doses If allergic, dapson, atovaquone, pentamidine
CMV Ganciclovir 5 mg/kg Q12H for 2 week induction Valganciclovir 900 mg Q12H
C difficile colitis Metronidazole (oral preferred) 500 mg Q8H Oral vancomycin
Typhlitis CefepimeAmikacinMetronidazoleFluconazole 2 gm Q8H7.5 mg/kg Q12H or qd500 mg Q8H400 mg qd
Candida CaspofunginAnidulafunginMicafungin 70 mg on day 1, then 50 mg qd200 mg on day 1, then 100mg qd100 mg qd If C. albicans, fluconazole is acceptable if susceptible

Antibiotics typically used for treatment of various infectious syndromes are noted below. Please note the doses are for adults with normal renal function and adjustments need to be made for impaired renal function; levels should be measured for vancomycin and amikacin and doses adjusted accordingly. Also take note that there are multiple drug interactions with chemotherapy and immunosuppressive drugs; doses of these various drugs need to be taken in consideration. For example, cyclophosphamide and vincristine should not be co-administered with voriconazole. Voriconazole potentiates the levels of cyclosporine, tacrolimus and sirolimus, and those drug doses need to be adjusted simultaneously with initiation of therapy. Consult the manufacturers’ packet for specific guidance.

2. Next list other key therapeutic modalities.

  • G-CSF has been shown to shorten neutropenia and reduce the risk for neutropenic febrile episodes, but it has not been shown to benefit neutropenic fever or infections once they occur.

  • Reduction of steroids and other immunosuppressives if possible improves the outcomes for fungal and viral infections.

  • Monitoring renal and liver function and blood counts are important to identify antibiotic toxicity

  • Normal saline is generally given to reduce renal toxicity of amphotericin products

  • Acetaminophen and diphenhydramine are frequently given prior to administration of amphotericin B infusions to reduce rigors

  • Red man’s syndrome can occur with vancomycin. Antihistamines before dosing and slowing the infusion can reduce recurrence of reactions

What complications could arise as a consequence of infection in recipients of hematopoietic cell transplantation?

What should you tell the family about the patient's prognosis?

  • Neutropenic fever: this is an expected complication, most respond well to empiric antibiotics; patients who deteriorate should be vigorously evaluated for resistant organisms (such as extended spectrum beta-lactamase producing Gram negative bacilli (ESBL), vancomycin resistant enterococcus (VRE), carbapenemase producing Klebsiella (KPC), methicillin resistant S. aureus (MRSA), and fungi.

  • Non-neutropenic fever: depends on specific etiology. Engraftment syndrome can be life threatening but usually responds to prompt administration of high dose steroids.

  • Pneumonia: Prompt assessment that includes invasive diagnostic procedure (usually bronchoscopy) is necessary for optimal treatment to achieve the best outcome.

  • Diarrhea: establishment of correct diagnosis is key to proper therapy. If due to GVHD or CMV this can be life threatening. If due to C. difficile, it should be amenable to treatment.

How can infection in recipients of hematopoietic cell transplantation be prevented?

  • Antibiotic prophylaxis is not beneficial for patients receiving chemotherapy regimens that cause short-term neutropenia (less than or equal to 7 days) (Table II). This would include most chemotherapy regimens used in solid tumor patients. In contrast, prophylaxis should be considered in patients who are receiving more intensive chemotherapy regimens expected to cause prolonged severe neutropenia expected to last at least 7-10 days. This would include treatment regimens typically used in the management of acute leukemia and patients undergoing allogeneic hematopoietic cell transplant using intensive myeloablative conditioning, and some intensive regimens for aggressive lymphomas. The antibiotic choices are discussed in consensus guidelines.

  • Neutropenic bacterial infections: Meta-analyses of several dozen randomized trials in neutropenic patients demonstrate a reduction in bacteremia, and recently mortality with fluoroquinolone prophylaxis. Accordingly, consensus statements generally recommend consideration of quinolone prophylaxis. However, concerns remain regarding emergence of drug resistance and association with resistant organisms, such as C. difficile and VRE. This is an especially great concern in particular institutions in which these infections are common. Caution is needed and longitudinal follow up with infection control is needed since patterns of resistance may change over time.

  • HSV: Acyclovir has been demonstrated to reduce the occurrence of HSV reactivation; in seropositive patients reactivation with oral ulcerations occurs in 70%, but this can be reduced to nearly zero with prophylaxis given until time of engraftment. Resistance to this short term use has been rare.

  • Zoster: Acyclovir, now more commonly valacyclovir, for one year has been shown to reduce the risk for zoster in seropositive patients from 40% to less than 5%. It should be continued beyond one year if the patient remains on immunosuppressive therapy.

  • PCP: Prophylaxis for 6 months (or longer if still on immunosuppressive therapy) is effective in prevention of PCP. Sulfamethoxazole-trimethoprim is most effective; breakthrough infections have been noted with the alternatives.

  • Fungi: Fluconazole has been demonstrated to reduce Candida infections and improve survival in randomized trials and is generally the antifungal prophylaxis of choice. However, in patients with prior mold infection, coverage for mold pathogens is important. Voriconazole has been best studied for this. Long term prophylaxis with itraconazole, voriconazole and posaconazole to cover both yeasts and molds, has been studied, but the benefit has been less well demonstrated and routine use of these agents is not regarded as standard. However, there are certain high-risk situations where consideration for use of these agents should be given: patients transplanted for acute myelogenous leukemia, longstanding antecedent neutropenia, iron overload, the occurrence of GVHD are such situations.

Table II.
Syndrome Antibiotic/drug Dose Alternative
Neutropenic fever G-CSFLevofloxacin 5 mg/kg/d750 mg/d ciprofloxacin
HSV Acyclovir 5 mg/kg IVQ8H or 400-800 mg POQ12H valacyclovir 500 mg PO QD
Zoster Valacyclovir 500 mg PO QD Acyclovir 800 mg PO Q12H
Candida Fluconazole 200-400 mg PO or IV QD micafungin
Aspergillus Voriconazole 200 mg BID PO posaconazole, liposomal amphotericin or ABLC
PCP pneumonia sulfamethoxazole-trimethoprim 1 DS tablet PO 3-4 doses per week If allergic, dapsone, atovaquone, pentamidine

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Freifeld, AG, Bow, EJ, Sepkowitz, KA. “Clinical practice guidelines for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 52. 2011. pp. 427-431. (IDSA Guidelines for clinicians regarding all aspects of prophylaxis and treatment of infections in patients who are neutropenic.)

Tomblyn, M, Chiller, T, Einsele, H. “Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplant Recipients: A Global Perspective”. Biol Blood Marrow Transplant. vol. 15. 2009. pp. 1143-1238. (International guidelines for prevention of infections among hematopoietic cell transplant recipients.)