Critical Care Medicine

Infections following organ transplantation (Including Solid Organ and Hematopoietic Stem cell): Presenting without localizing signs

Fever, without localizing signs; with or without neutropenia, and with or without hypotension, in a transplant recipient

Neutropenic fever; Febrile neutropenia; Undifferentiated fever; Fever of unknown origin; Disseminated infection; Sepsis

Cytomegalovirus (CMV) viremia, Epstein-Barr virus (EBV) viremia, parvovirus, influenza, adenovirus, human herpesvirus-6, bacteremia, transplant pyelonephritis, listeriosis, biliary sepsis, catheter-associated bloodstream infection, fungemia, cryptococcosis, candidiasis, candidemia, aspergillosis, histoplasmosis, mycobacterial infection, nontuberculous mycobacteria, tuberculosis, allograft rejection, graft-vs-host disease, post-transplant lymphoproliferative disease, thromboembolic disease, adrenal insufficiency, medication reaction, and transplant-associated thrombotic microangiopathy (TMA) may all occur with minimal localizing signs, at least initially.

1. Description of the problem

What every clinician needs to know

Solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients are vulnerable to a wide variety of infections: bacterial, fungal, viral or parasitic. Some of these present primarily with systemic signs such as fever, chills and drenching sweats, without other localizing symptoms (although organ involvement may be discovered on subsequent investigation). The clinician should be familiar with both common and rare causes of this presentation (listed above).

Neutropenia may be present, particularly in HSCT recipients prior to engraftment or with failure to engraft, and SOT recipients who have CMV viremia or who are receiving medications that cause leukopenia (e.g. mycophenolate mofetil, azathioprine, valganciclovir or ganciclovir). Hypotension may be present, especially in bacteremias, fungemias, and impending sepsis. The presence of neutropenia and/or hypotension make the clinical situation more urgent, since the immunocompromised host can rapidly deteriorate in this setting.

Clinical features

Fever is often the most prominent symptom; chills and sweats may or may not be present. Shaking chills suggest bacteremia, fungemia or viral syndromes such as influenza. Respiratory, gastrointestinal, central nervous system, and cutaneous presentations of infection in this patient population are discussed in separate sections of this text. Catheter-associated bloodstream infection may be occult when there are no signs or symptoms referable to the catheter (e.g. no exit site erythema, drainage or tenderness, and no tunnel tenderness). Generalized weakness, fatigue and anorexia are often seen.

Key management points

Particularly if neutropenia is present in the febrile transplant patient, appropriate cultures should be obtained rapidly, and broad-spectrum antibiotic coverage must be initiated as soon as possible, regardless of the presence or absence of a suspected source of infection (see below).

2. Emergency Management

Emergency management steps

For the febrile neutropenic patient, Gram-negative coverage is mandatory and should include at least one or more agent(s) that cover Pseudomonas (e.g., piperacillin-tazobactam, ceftazidime, cefepime, imipenem, meropenem, tobramycin or amikacin) based on local antimicrobial resistance patterns at that particular center, or on antimicrobial susceptibilities from the patient's previous known cultures. Some centers use monotherapy and some use dual therapy to cover Gram-negative bacteria.

The use of an agent for MRSA coverage in the initial regimen (e.g., vancomycin) has been a controversy in the fever/neutropenia literature and practices differ; however, in a patient who is severely ill and/or with suspicion of catheter-related infection, particularly at centers with high incidence of MRSA infection, it is reasonable to include vancomycin while awaiting culture results.

Antifungal coverage has traditionally been reserved for the neutropenic patient whose fever has not responded after several days of broad-spectrum therapy; however in the critically ill patient or a patient with an intra-abdominal process or with known prior candidal or mold colonization, it is often desirable to add antifungal coverage (an azole, echinocandin or amphotericin derivative) since candidemia may be present and cultures may not grow for several days. Be aware that echinocandins do not cover Cryptococcus or Histoplasma.

Emergency management checklist

  • Obtain blood cultures rapidly from each lumen of the indwelling IV catheter (if present) and a peripheral vein.

  • As soon as blood cultures are drawn, initiate broad-spectrum intravenous antibiotics (see above).

  • Send a swab culture of any drainage from line sites, incisions or ulcerations.

  • Obtain a urinalysis and urine culture.

  • Perform a chest X-ray.

  • Obtain CBC with differential and a chemistry panel including renal and liver function tests, if not already done.

3. Diagnosis

Diagnostic criteria and tests

Besides the initial tests listed above, other blood tests which may be obtained according to the individual patient's situation include a cytomegalovirus (CMV) quantitative PCR; Epstein-Barr virus (EBV) quantitative PCR; parvovirus PCR; human herpesvirus-6 PCR (particularly in the neutropenic HSCT patient); cryptococcal antigen; Histoplasma antigen; fungal antibody panel; Aspergillus galactomannan antigen; beta-d-glucan, fungal isolator blood culture; and mycobacterial isolator blood culture.

Other urine tests that may be helpful include the Histoplasma urinary antigen, Legionella urinary antigen and urine fungal culture.

Nasopharyngeal swab for respiratory viruses (including influenza, parainfluenza, adenovirus, respiratory syncytial virus, and metapneumovirus) may be helpful, particularly in the setting of seasonal outbreaks.

If a bronchoalveolar lavage (BAL) is performed, stains and cultures or PCR should be performed at least for: routine bacteria, Legionella, Nocardia, fungi, mycobacteria, Pneumocystis, cytomegalovirus, and respiratory viruses, as well as BAL Aspergillus galactomannan antigen if available.

In the presence of persistent positive blood cultures, especially those known to cause endovascular infections (staphylococci, streptococci, enterococci, Candida spp), echocardiogram and ultrasound of the upper extremity veins (to rule out septic thrombophlebitis in patients with indwelling catheters) are appropriate.

Normal lab values

Normal WBC count is approximately 4,000-10,000 cells/ul. An absolute neutrophil count (ANC) of fewer than 1,000 (sometimes fewer than 500) is considered indicative of neutropenia. The degree and duration of neutropenia correlate with severity of disease; an ANC of less than 100 indicates a more profound immune defect than an ANC of 900, for example. Neutropenia that is of short duration with rapid recovery following chemotherapy for a solid tumor would generally be less dangerous than neutropenia after induction chemotherapy for leukemia, for example (which may last for several weeks).

Neutropenia after an autologous HSCT (where the patient's own peripheral blood stem cells or bone marrow is reinfused) is generally shorter than after an allogeneic HSCT (in which the patient receives peripheral stem cells or bone marrow from another individual, and reconstitutes their immune system from their donor's cells). Neutropenia lasts on average 10 days after an autologous HSCT; 2-3 weeks after an allogeneic HSCT, and can be even longer (4-5 weeks) after a cord blood transplant.

For a neutropenic solid organ transplant recipient, administration of filgrastim (G-CSF) can shorten the duration of neutropenia; it appears to be safe and does not precipitate rejection. For the HSCT recipient, filgrastim should be used under the guidance of a hematologist.

Establishing a diagnosis

The causes of undifferentiated fever are many, but can be narrowed down by understanding the classic timetable of expected infections after solid transplantation (as expounded by Rubin and Fishman). For solid organ transplantation, the timetable is divided into three periods. In the first month, infections seen are mostly those that can occur after any major surgery; in addition, oral candidiasis and mucosal herpes simplex (HSV) reactivation are common.

Consequences of anatomic problems such as bile leaks in liver transplant recipients or airway dehiscence in lung transplant recipients may be seen during this time and may predispose to infections. In the second time period, that of the 2nd-6th month post-transplant, the opportunistic infections considered characteristic of transplantation are more likely to occur (CMV, aspergillosis, etc).

The highest risk patients for these opportunistic infections are those who have experienced rejection and intensified immunosuppression; or those who are donor seropositive, recipient seronegative (D+/R-) for an organism (CMV for example), since they have no pre-existing immunity but can acquire a new infection from their donor.

In the third time period, more than 6 months post-transplant, patients are divided into three groups. The first group are those that have done well and immunosuppressive agents have been tapered; the second group is on more than the usual immunosuppression due to previous rejection. Those in the former group are less likely to have opportunistic infections, but still may have severe versions of common infections such as influenza, pneumococcal pneumonia and urinary tract infections.

Those in the latter group are extremely immunosuppressed and remain subject to all of the opportunistic infections seen in the second time period. Those in the third group may initially do well with their allograft function, but then the effects of long-term viruses begin to take their toll (hepatitis B and C; BK polyomavirus; late CMV; human papillomavirus), and these pathogens can confer additional immunosuppression or may have adverse consequences for the transplanted organ.

For HSCT/bone marrow transplantation, there are also three time periods but they are somewhat different from the timetable for solid organ transplantation above. During the first period or pre-engraftment period, the patient is neutropenic and is vulnerable to a variety of bacterial and fungal infections (see above). During the second or early post-engraftment period, the WBC has recovered but the patient's immune system is not yet fully functional. Acute graft-versus-host disease (GVHD) of the skin, GI tract or liver may occur.

GVHD requires high-dose immunosuppressive therapy and thus renders the patient more vulnerable to infections. In the third or late post-engraftment period, patients may have chronic GVHD of the skin, mucous membranes, eyes, or lungs; they remain vulnerable to infections particularly with encapsulated bacterial organisms such as Pneumococcus and Hemophilus species; hypogammaglobulinemia is common.

In the absence of prophylaxis, CMV infection including CMV pneumonitis is most common from 50 to 100 days after HSCT, but may occur at any time, especially in the patient with more than usual immunosuppression or who is donor seronegative, recipient seropositive (D-/R+) for CMV, since the immune system is reconstituted from a donor who has never been exposed to CMV (note this is the opposite of the high-risk group for solid organ transplantation which is D+/R-).

Invasive fungal infections including aspergillosis and mucormycosis may occur during the neutropenic phase or later during immunosuppressive therapy for GVHD, especially in the setting of environmental exposures such as construction or gardening.

Other possible diagnoses

In addition to the infections listed above, there are multiple noninfectious causes of undifferentiated fever in this population. Solid organ transplant allograft rejection may be manifested by fever before overt dysfunction of the organ is noted. Acute graft-vs-host disease in HSCT recipients usually has findings localizing to skin, the GI tract or liver, but occasionally may be heralded by fever alone. Drug fevers (from antibiotics such as vancomycin, beta-lactams or sulfa; immunosuppressives such as sirolimus; anticonvulsants, etc.) may occur with or without rashes.

Transfusion reactions may involve fevers. Neoplasms may present with fever, particularly post-transplant lymphoproliferative disease (PTLD) which is often, though not always, associated with EBV. Adrenal insufficiency may result from steroid withdrawal or from infection (TB, histoplasmosis). Transplant-associated thrombotic microangiopathy (TMA), primarily associated with the calcineurin inhibitors cyclosporine and tacrolimus, and occasionally with sirolimus, may involve fever as well as low hemoglobin, thrombocytopenia and red cell fragments on the peripheral blood smear.

Confirmatory tests

In addition to the cultures and PCRs above, CT scans of the chest, abdomen, and pelvis are frequently performed in immunocompromised patients with fever. The chest CT may reveal adenopathy; lung abscess; septic emboli; pulmonary nodules (with or without cavitation and the halo sign) suggesting fungal, nocardial or mycobacterial infection; a miliary pattern indicative of disseminated histoplasmosis, tuberculosis or other granulomatous infection; or other subtle features not seen on standard chest X-ray.

The abdominal/pelvic CT may show abscesses or other nonanatomic fluid collections such as lymphocoeles, urinomas, hematomas or bilomas; biliary dilatation; intestinal wall thickening; venous or arterial thromboses; masses; adenopathy; granulomata; and other clues to fever source.

If all of the above are unrevealing and fevers persist with negative cultures despite broad-spectrum antibacterials and the addition of antifungal therapy, a tagged WBC scan or PET CT scan is sometimes helpful in localizing an occult source. Ultrasounds of the upper and lower extremity veins are helpful, as deep venous thromboses can cause fever and may represent septic thrombophlebitis in the presence of an indwelling catheter.

Transthoracic echocardiogram may be performed to rule out endocarditis or pericardial effusion. Although the transesophageal echo is more sensitive for detection of endocarditis, it may not be able to be performed due to thrombocytopenia and bleeding risk, or varices in some liver transplant patients.

4. Specific Treatment

As described above, antimicrobial therapy for the febrile neutropenic transplant recipient should include at least one agent with activity against Gram-negative bacteria, including Pseudomonas, and may consist of dual therapy or monotherapy depending on local custom and antimicrobial resistance patterns. Use of MRSA coverage such as vancomycin in the initial regimen for febrile neutropenia has been debated, but it is reasonable to include in the very ill patient or one with signs indicative of possible catheter-related infection.

Drugs and dosages

Dosages of antimicrobials should be maximal within the indicated range (especially for neutropenic or septic patients) but should be adjusted for renal dysfunction according to the manufacturers' instructions. The following list includes some commonly used antibiotics in this setting, though it is not comprehensive; doses given are for normal renal function and should be adjusted for renal dysfunction according to the manufacturer's nomogram.

  • Acyclovir 5 mg/kg IV Q8h (mucosal HSV in an immunocompromised patient); 10 mg/kg IV Q8h (for disseminated zoster in an immunocompromised patient or one unable to take oral medications); acyclovir 400 mg po BID (e.g.) for prophylaxis.

  • Amphotericin B Lipid Complex (ABLC) or Liposomal Amphotericin B - prophylaxis 3 mg/kg/day, treatment 5 mg/kg/day (premedication generally with acetaminophen, diphenhydramine, +/- hydrocortisone, normal saline).

  • Amikacin - regimens vary depending on traditional or extended interval dosing (use manufacturer's nomogram) and adjust to maintain trough level at less than 8 and peak 28-35 mcg/ml (for pneumonia or sepsis).

  • Anidulafungin 200 mg IV loading dose followed by 100 mg IV once daily.

  • Azithromycin 500 mg IV daily.

  • Aztreonam 1-2 g IV Q6-8h.

  • Caspofungin 70 mg IV x 1 dose then 50 mg IV Q12h.

  • Cefazolin 1 g IV Q8h.

  • Cefepime 2 g IV Q8 h.

  • Ceftazidime 1-2 g IV Q8h.

  • Ceftriaxone 1 g IV Q24h (higher for endocarditis or meningitis).

  • Ciprofloxacin 400 mg IV Q12h.

  • Clindamycin 600-900 mg IV Q8h.

  • Colistimethate 100-125 mg IV Q6-12h (generally reserved for MDR organisms - especially important to adjust for renal dysfunction per manufacturer's nomogram - watch for nephrotoxicity).

  • Cytomegalovirus immune globulin (CMVIg) 100 mg/kg-150 mg/kg IV (premedication generally with acetaminophen, diphenhydramine, +/- hydrocortisone; dosing schedules vary; used for hypogammaglobulinemia or adjunctive therapy for tissue-invasive CMV disease such as CMV pneumonitis).

  • Daptomycin 6 mg/kg IV Q24h.

  • Filgrastim (G-CSF) 300 mcg SQ or 480 mcg SQ can be administered daily as needed for neutropenia in the solid organ transplant recipient (it does not appear to precipitate rejection in this setting). Filgrastim should be used under the guidance of a hematologist in the HSCT recipient. When filgrastim is stopped the WBC count may fall by up to 50%.

  • Fluconazole 100-400 mg IV Q24h.

  • Foscarnet - follow manufacturer's nomogram.

  • Ganciclovir 5 mg/kg IV Q12h (therapy) or 5 mg/kg IV Q24h (prophylaxis).

  • Gentamicin - regimens vary depending on traditional or extended interval dosing (use manufacturer's nomogram) and adjust to maintain trough level at less than 2 and peak 7-10 mcg/ml (for pneumonia or sepsis).

  • Imipenem 500-1000 mg IV Q6h.

  • Intravenous immunoglobulin (IVIg) 400 mg/kg IV per dose; number and timing of doses varies; with acetaminophen/diphenhydramine (and sometimes hydrocortisone) premedication - used for hypogammaglobulinemia or adjunctive therapy for tissue-invasive CMV disease such as CMV pneumonitis.

  • Isavuconazole 372 mg po/IV Q8h for 6 doses, then 372 mg po/IV Q24h.

  • Itraconazole 200 mg Q12h.

  • Levofloxacin 500 mg-750 mg IV Q24h.

  • Linezolid 600 mg IV Q12h.

  • Meropenem 500 mg IV Q6h-1 gram IV Q8h.

  • Metronidazole 500 mg IV Q6-8h.

  • Micafungin 100-150 mg IV Q24h.

  • Moxifloxacin 400 mg IV Q24h.

  • Oxacillin 1-2 g IV Q4-6h.

  • Piperacillin-tazobactam 3.375 grams IV Q6h-4.5 grams IV Q6h.

  • Posaconazole. Extended – release formulation preferred: 300 mg po Q12 x 2 doses, then 300 mg po daily. If necessary to administer via tube, use the liquid formulation, 200 mg po four times daily (treatment dose) or 200 mg po three times daily (prophylaxis) – which must be given with food containing fat.

  • Tigecycline 100 mg IV x 1 dose followed by 50 mg IV Q12h.

  • Tobramycin - regimens vary depending on traditional or extended interval dosing (use manufacturer's nomogram) and adjust to maintain trough level at less than 2 and peak 7-10 mcg/ml (for pneumonia or sepsis).

  • Trimethoprim-sulfamethoxazole one double-strength po daily or thrice weekly for Pneumocystis prophylaxis; 15-20 mg/kg/day of the trimethoprim component (divided Q6h) for treatment of Pneumocystis pneumonia.

  • Vancomycin 1-1.5 grams IV Q12h with subsequent pre-dose levels and appropriate adjustment.

  • Valganciclovir 900 mg po BID for treatment and 450 mg po BID (or 900 mg po daily) for prophylaxis.

  • Voriconazole 6 mg/kg po/IV Q12h x 2 doses then 4 mg/kg IV Q12h, with a level on Day 5 (aiming for level 2 – 5). Note that azole antifungals and some macrolides (erythromycin, clarithromycin) raise the levels of cyclosporine, tacrolimus, sirolimus, and everolimus, and require close monitoring and adjustment of levels and doses of those agents. Azithromycin is the preferred macrolide in patients receiving these immunosuppressive agents, as the interaction is minimal. Also note that aminoglycosides may have enhanced nephrotoxicity in patients receiving cyclosporine or tacrolimus, and alternative agents should be considered if appropriate microbiologically. Assistance of a pharmacist familiar with transplant-related issues is very helpful.

Refractory cases

For refractory cases, consider invasive fungal infection and add or change the antifungal agent; consider possible resistant bacteria (such as extended-spectrum beta-lactamase producing (ESBL) E. coli and Klebsiella; carbapenemase-producing Klebsiella (KPC); carbapenem-resistant Acinetobacter baumanii (CRAb); Burkholderia cepacia; Stenotrophomonas; multiresistant Pseudomonas; etc. Repeat cultures to see if a new organism will be identified; but if not, or if the patient has a clinically worsening course before culture results are available, additional agents such as tigecycline, intravenous colistin or amikacin may need to be added empirically for the possibility of multiresistant organisms (see above for dosing).

Look for viral infections such as CMV, EBV, human herpesvirus-6 and parvovirus in transplant recipients with fever and negative cultures; consider noninfectious causes such as drug fever, GVHD and transplant-associated thrombotic microangiopathy.

5. Disease monitoring, follow-up and disposition

Monitoring

Depending on the cause, it is to be hoped that with appropriate antimicrobial coverage, fever and hypotension will improve within 48 hours; however, for some neutropenic patients, fevers continue for a long period of time or until the return of a more normal WBC count. If a pathogen is identified and the patient is not neutropenic, antibiotic coverage may be de-escalated and focused, but if the patient remains neutropenic, broad-spectrum coverage is still necessary to protect against Gram-negative bacilli.

For example if a neutropenic, febrile patient grows MRSA from a blood culture, vancomycin should be given in conjunction with another agent(s) that provides Gram-negative coverage. In patients receiving combinations of multiple antibiotics, rashes may occur and may necessitate changing or discontinuing different antibiotics while still maintaining protective broad coverage until neutropenia resolves.

Incorrect diagnosis

If the patient continues to be severely hypotensive on antibiotic therapy appropriate for the organism(s) growing in culture, suspect "pus under pressure" such as undrained infection in the urinary or biliary tract. Persistent positive blood cultures despite appropriate antibiotic therapy suggest a persistent endovascular focus such as endocarditis or septic thrombophlebitis (occasionally another source, such as vertebral osteomyelitis, can also lead to persistent bacteremia.)

Worsening clinical status may also indicate that the patient's initial infection has been complicated by superimposed C. difficile infection or a second bacterial, fungal, or viral infection, possibly with a more resistant organism, particularly in the setting of long hospital/ICU stay. CMV reactivation often occurs 1-3 weeks after bacterial infection since cytokines stimulate CMV replication, so persistent or recurrent fever after bacterial infection should prompt testing for CMV viremia.

Follow-up

If a specific infection is identified, such as a bacteremia or candidemia, repeat blood cultures should be performed while on therapy until these cultures clear. If the cultures do not clear on therapy, consider endocarditis, septic thrombophlebitis or another fixed focus. Then it is desirable to repeat blood cultures again, at least several days after completion of antibiotic therapy, to make sure that the infection has resolved. This is particularly important if it is a catheter-related infection that has been treated with the catheter in place, in which case the followup cultures should be drawn through the catheter for "proof of cure."

If CMV viremia was identified, weekly monitoring of the quantitative CMV viral load should be performed to help guide duration of therapy.

Pathophysiology

Neutrophils are important for control of bacterial and fungal infections. Hematopoietic stem cell transplantation involves the administration of high-dose chemotherapy and then infusion of the patient's own (autologous) or another individual's (allogeneic) stem cells or bone marrow, or cord blood, and involves a period of neutropenia. The patient's immune system is then reconstituted from either their own (autologous) or another's (allogeneic).

The process of recovery of immune function takes months beyond the time of engraftment (recovery of the WBC count), as many functions of the immune system take more time to re-develop. For example, hypogammaglobulinemia, including both immunoglobulin class and subclass deficiencies, is common during the first post-transplant year and sometimes for years afterwards, particularly in allogeneic HSCT recipients with graft-vs-host disease.

For solid organ transplant recipients, powerful immunosuppressive medications are administered to prevent graft rejection (and many of these are also used for prevention and treatment of GVHD in solid organ transplant recipients.) These medications include prednisone, methylprednisolone, cyclosporine, tacrolimus, mycophenolate, azathioprine, sirolimus, thymoglobulin, alemtuzumab and others.

These variously affect aspects of cellular immune function. including some that target T cell activation and proliferation (cyclosporine, tacrolimus), some that have powerful antilymphocyte properties (thymoglobulin, alemtuzumab), some that affect function of both B and T cells and are antimetabolites (mycophenolate, azathioprine), and some that are antiproliferative (sirolimus).

All of these predispose to infection by impairing usual host defenses; for example, therapies that decrease T cell numbers or function can affect defenses against viral infection in the form of virus-specific cytotoxic T lymphocytes. If a patient is both neutropenic and receiving one or more of these agents, the degree of immunosuppression is often even greater.

Further information is available on the specific effects of particular immunosuppressive agents and types of infections that they predispose to (see Fishman and Rubin; Issa and FIshman). Assessment of the patient's global immune function with IgG levels, lymphocyte subsets, and/or in vitro lymphocyte stimulation testing may be helpful in guiding reduction of immunosuppression and in addressing remediable immunologic defects (such as hypogammaglobulinemia with IVIg, or neutropenia with filgrastim.)

Epidemiology

Epidemiology of bacterial infections in transplant recipients in recent years has been dominated by the emergence of antimicrobial resistance, with increasing emphasis on pathogens such as MRSA, VRE, multiresistant Pseudomonas, carbapenemase-producing Klebsiella (KPC), Stenotrophomonas, and carbapenem-resistant Acinetobacter (CRAb). Extensive use of antimicrobials likely predisposes to such resistance, and many centers have programs of antimicrobial stewardship (as well as infection control policies) designed to reduce the incidence of such pathogens.

However, in the extremely ill patient, very broad coverage is appropriate depending on local resistance patterns and the patient's own risk factors. De-escalation or focusing of antibiotic therapy should be considered once initial culture results have been obtained, although adequate broad coverage for the neutropenic patient should be maintained. Local infection control policies should be rigorously followed, including isolation precautions.

The presence of any surgical-anatomical problems increases risk for infection (bile leaks or strictures, urinomas, lymphoceles, airway necrosis or dehiscence, hematomas, bilomas). The presence of indwelling foreign bodies, though often necessary, may also provide a nidus for infection (biliary drainage catheters, urinary stents, airway stents) and may also precipitate flares of infection during catheter change and removal.

Presence of comorbidities such as diabetes, renal dysfunction and need for renal replacement therapy, other organ dysfunction, respiratory failure and need for prolonged mechanical ventilation, malnutrition and other concomitant conditions increases risk for post-transplant infections.

Epidemiology of invasive fungal infections is changing over time, with more successful prevention and treatment of aspergillosis, but persistent high mortality from non-Aspergillus mold infections. In solid organ transplant recipients, a 17-center study by Neofytos et al found that invasive candidiasis was the most common invasive fungal infection overall (59%), followed by aspergillosis (25%), cryptococcosis (7%), and other molds (6%), but in lung transplant recipients, invasive aspergillosis was the most common fungal infection (likely do to constant exposure of the lung allograft to the outside environment).

In contrast to invasive candidiasis, which frequently occurred in the early post-transplant period, aspergillosis in lung recipients tended to occur more than 1 year post-transplant. Liver recipients with invasive fungal infections had the highest mortality.

Symptomatic CMV disease is less frequently seen with the advent of prophylaxis and pre-emptive therapy for CMV, but still may occur, and "late CMV" (occurring more than 6 months post-transplant) and ganciclovir-resistant CMV are continuing challenges. Risk factors for severe CMV disease include D+/R- (donor seropositive, recipient seronegative) status in solid organ, and D-/R+ status in HSCT recipients.

Therapy for rejection, particularly use of antilymphocyte therapy, increases subsequent risk for CMV, EBV (including PTLD) and other viral infections. Ability to assess cellular immune function specific to CMV and other viruses will aid in control of these infections and prediction of which patients are at highest risk.

Prognosis

Prognosis will vary widely depending on the cause of fever, the degree and duration of neutropenia (if present), the doses and agents utilized for immunosuppression, and other comorbidities including multiorgan dysfunction, need for renal replacement therapy, diabetes, extremes of age, disruption of skin and mucous membrane barriers. Ability to resolve neutropenia and/or to restore other aspects of immune function by reducing immunosuppression can be crucial in resolving a severe infection.

Special considerations for nursing and allied health professionals.

NA

<b>What's the evidence?</b><b>Neutropenic fever or other causes of fever in HSCT/bone marrow transplant recipients</b>EngelhardDCordonnierCShawPJ et al. Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey. Br J Haematol2002;117:444-50.

(Multicenter study of an important pathogen in HSCT recipients, particularly in the late post-transplant period in patients with graft-vs-host disease.)

FreifeldAGBowEJSepkowitzKA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis2011; 52:e56-e93.Gea-BanaclocheJCWadeJC. Improvements in the prevention and management of infectious complications after hematopoietic stem cell transplantation. Cancer Treat Res2009;144:539-73.

(Overview of modern infection prophylaxis and changing patterns of infection in HSCT recipients over time.)

HornDLFishmanJASteinbachWJ et al. Presentation of the PATH alliance registry for prospective data collection and analysis of the epidemiology, therapy and outcomes of invasive fungal infections. Diagn Microbiol Infect Dis2007;59(4):407-14.

(Data from the Prospective Antifungal Therapy Alliance about 1,700+ patients.)

MossadSBAveryRKLongworthDL et al. Infections complications within the first year after nonmyeloablative allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant2001;28:491-5.

(One of the earliest series of infections after reduced-intensity HSCT.)

<b>Effects of particular immunosuppressive agents</b>IssaNCFishmanJA. Infectious complications of antilymphocyte therapies in solid organ transplantation. Clin Infect Dis2009;48:772-86.

(Particular infectious risks from lymphocyte-depleting therapies such as OKT3 and antithymocyte globulin.)

<b>Timetable of infection, risk factors, and causes of fever in solid organ transplant recipients</b>*The reader is referred to the American Society of Transplantation Guidelines for Management of Infection in Solid Organ Transplant Recipients, published as a supplement to the American Journal of Transplantation (3rd edition, 2013) which has multiple chapters on specific pathogens, specific syndromes, donor-derived infections, drug interactions, immunizations, and strategies for safer living. An example is the CMV section below.AveryRK. Infections after lung transplantation. Semin Respir Crit Care Med2006;27(5):544-51.

(Overview of infections in lung transplant recipients, including special considerations relating to airway complications, and donor and recipient pretransplant colonizations.)

FishmanJARubinRH. Infection in solid-organ transplant recipients. N Engl J Med1998;338(24):1741-51.

(Classic article that presents the paradigm of the three-part timetable of infections after solid organ transplant.)

RazonableRRHumarA. Cytomegalovirus in solid organ transplantation. Am J Transplant2013; 13:93-106.

(Current guidelines pertaining to CMV, from the American Society of Transplantation.)

HusainSAlexanderBDMunozP et al. Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi. Clin Infect Dis2003;37:221-9.

(Documents the emergence in recent years of molds other than Aspergillus.)

MawhorterSYamaniMH. Hypogammaglobulinemia and infection risk in solid organ transplant recipients. Curr Opin Organ Transplant2008;13:581-5.

(Reviews an interesting body of work on de novo post-transplant hypogammaglobulinemia as an underappreciated risk factor for post-transplant infections.)

NeofytosDFishmanJAHornD et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis2010;12:220-9.

(Microbiology and mortality of invasive fungal infections in more than 400 solid organ transplant recipients from 17 centers.)

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