Critical Care Medicine

Infections following organ transplantation (Including Solid Organ and Hematopoietic Stem cell): CNS and head-and-neck infections

Meningitis, encephalitis, meningoencephalitis, brain abscess, complicated sinusitis, complicated otitis, rhinocerebral mucormycosis or aspergillosis, head and neck infections, head and neck zoster

Synonyms

Central nervous system infections in the immunocompromised host; mental status changes in the immunocompromised host; intracerebral infections in the immunocompromised host; meningeal infections in the immunocompromised host; sino-orbital infections in the immunocompromised host

Related conditions

Fever/neutropenia; invasive fungal infection, listeriosis, bacterial meningitis, pneumococcal meningitis, cryptococcal meningitis, fungal meningitis, viral meningitis, CMV or HHV-6 encephalitis, JC virus, progressive multifocal leukoencephalopathy, facial zoster, Ramsay-Hunt syndrome, actinomycosis, malignant external otitis, tuberculous meningitis, cranial nerve palsies, orbital cellulitis, orbital abscess, orbital apex syndrome, cavernous sinus thrombosis, CMV retinitis, post-transplant lymphoproliferative disease, calcineurin inhibitor toxicity, antimicrobial toxicity, thrombotic microangiopathy, posterior reversible encephalopathy syndrome, confusion, delirium, hallucinations, intracerebral haemorrhage

1. Description of the problem

What every clinician needs to know

Infections involving the central nervous system (CNS) and/or the head and neck are serious concerns, particularly in the neutropenic patient. A wide variety of pathogens can cause meningitis, encephalitis or meningoencephalitis in the immunocompromised host. Certain invasive fungal infections such as mucormycosis and aspergillosis can rapidly progress from the sinonasal area to the orbits and brain, conferring a high mortality.

Any transplant recipient or neutropenic patient with signs or symptoms referable to the CNS or to the sinuses, eyes and ears, should be treated as a potential emergency, and immediate surgery can be life-saving in such situations. Mental status changes may accompany these infections or may be signs of medication toxicity or sepsis originating in another organ system.

Clinical features

Signs and symptoms to look for include: headache, fever, neck stiffness, mental status changes (confusion, delirium, lethargy, coma), dizziness, ataxia, seizures, focal neurologic signs such as weakness or numbness, diplopia, proptosis, chemosis, blurry vision, pain or pressure in the maxillary or frontal sinus area, periorbital or facial swelling, cranial nerve palsies, extraocular movement limitation, ear pain or ear canal drainage, enlarged neck lymph nodes, rash on the head or neck, oral or pharyngeal ulcerations, tonsillar swelling or erythema, dark lesions in the nose or pharynx, oral mucositis, swelling of the tongue or floor of the mouth, toothache, gum inflammation.

2. Emergency Management

Emergency management steps

  1. Assess the patient rapidly with a neurologic exam including the cranial nerves, paying particular attention to limitations of extraocular motion, proptosis and periorbital edema. Meningismus may not be present in the neutropenic patient with meningitis.

  2. For patients with impaired mental status, rapidly rule out metabolic causes such as hypoglycemia, hyponatremia, and hypoxemia. Control seizure activity if present.

  3. Obtain cultures of blood (including through central or indwelling IV catheters), urine and other sites according to the clinical presentation, since sepsis from any origin can present with mental status changes.

  4. Initiate broad-spectrum antibiotic therapy (see below) in patients who are neutropenic or who have suspected meningitis, sinusitis, orbital infections or other invasive bacterial infections. Consider empiric antifungal therapy in neutropenic patients or those with suspected fungal sino-orbital or intracranial disease. Start antiviral therapy (intravenous acyclovir, see below) for suspected head and neck zoster or disseminated zoster.

  5. Obtain imaging of the brain, sinuses and orbits if the patient is stable enough (MRI or CT); if contrast can be administered, this provides more information regarding brain abscesses and white matter changes (e.g., calcineurin inhibitor toxicity); however in the thrombocytopenic patient or others at risk for intracranial hemorrhage, a non-contrast brain CT is often obtained first to rule out hemorrhage.

  6. Consider lumbar puncture if brain imaging has indicated that this would be safe (no impending herniation, hydrocephalus, etc.) and if the platelet count can be transfused to an adequate level in a thrombocytopenic patient.

  7. Consider emergent neurology, neurosurgery, ENT, and/or ophthalmology consultation if the patient exhibits a focal neurologic defect, has a space-occupying lesion on imaging, has evidence of increased intracranial pressure, has evidence of orbital cellulitis or abscess (limitations of extraocular motion, proptosis), or evidence of malignant external otitis or mastoiditis (pain, swelling, drainage around the ear or from the ear canal).

  8. For suspected meningitis, or localized or disseminated zoster, follow your center's Infection Control guidelines for isolation precautions.

Checklist

  • Neurologic and mental status exam.

  • Rule out metabolic causes (hypoglycemia, hyponatremia, hypoxemia).

  • Control seizure activity.

  • Culture blood, urine, other sites as indicated.

  • Initiate antimicrobials (see below) if the patient is neutropenic or if bacterial, fungal or viral infection is suspected.

  • Obtain imaging of the brain, sinuses and orbits.

  • Consider LP if brain imaging does not show a contraindication and if the platelet count is adequate.

  • Consider emergent neurology, neurosurgery, ENT, or ophthalmology consult.

  • Follow Infection Control guidelines for your center regarding isolation.

3. Diagnosis

Diagnostic criteria and tests

As described above, cultures of blood and urine should be obtained (also stool or respiratory specimens as the clinical situation dictates), since sepsis from sources outside the CNS can present with mental status changes.

CNS imaging is very important. Non-contrast CT scanning can be rapidly obtained to rule out intracranial hemorrhage; however MRI (with contrast if possible) is preferable for delineating lesions such as brain abscesses (fungal, bacterial, Nocardia), embolic lesions, white matter changes of progressive multifocal leukoencephalopathy, etc.

If an LP is judged safe to perform (with regards to risk of herniation, platelet count, etc.), considerable additional information may be obtained. The CSF should be sent for cell count and differential, protein, glucose, cytology, Gram stain and culture, fungal stain/cryptococcal antigen/fungal culture, AFB stain/AFB culture and VDRL.

Ideally, viral PCRs (e.g., HSV, VZV, CMV, EBV, human herpesvirus-6 and -7, JC virus, West Nile virus or others) should be obtained on CSF as well. Viral cultures from CSF are low-yield and have largely been replaced by PCRs. PCR for Toxoplasma can also be sent on CSF and is a better test than antibody titers. CSF cytology is important in diagnosing malignancies such as carcinomatous or lymphomatous meningitis, which may mimic CNS infections.

Noninvasive testing for CNS infections also can include: blood cryptococcal antigen, Aspergillus galactomannan antigen, blood beta-d-glucan, Histoplasma urinary or blood antigens, fungal antibody panel, blood quantitative PCRs for CMV, EBV, HHV-6 and 7, West Nile virus, JC virus, toxoplasmosis, etc. However, in some cases of these infections, only the CSF is positive, not the blood PCR or antigen testing.

Antibody titers for viral infections are often of limited value in acutely ill transplant recipients. For example, IgG will be positive for the majority of the population for such viruses as VZV, HHV-6, EBV and CMV. However, transplant recipients may not mount an IgM response even in the setting of an active infection. A positive viral IgG with negative IgM is not helpful diagnostically. PCR testing is much more helpful for diagnosis of active viral infection when available. On the other hand, antibody serologic testing is frequently obtained when Lyme borreliosis or syphilis is suspected as a possible cause of CNS infection.

Differential diagnosis

Epidemiologic exposures can be helpful in focusing the differential diagnosis. Listeria meningitis is most common in very young, very old, pregnant, or immunocompromised patients, and is usually foodborne (nonpasteurized dairy foods, soft cheeses, hot dogs, turkey franks, deli meats, etc). Consumption of raw meat and/or handling of kitty litter suggest toxoplasmosis.

History of past tuberculosis or latent TB infection without treatment may suggest reactivation of TB in the CNS. Exposure to farms, chickens, birds or outdoors exposures early in life may suggest reactivation of histoplasmosis. Similar outdoors or construction exposures may lead to colonization of the sinuses with other fungi such as Aspergillus, which may become invasive under the influence of neutropenia or immunosuppression. Tick bites suggest Lyme borreliosis or infection with Rickettsia spp, Ehrlichia, or Anaplasma.

Neutropenia predisposes to invasive fungal infections; presence of uncontrolled diabetes is also a risk factor for fungal infections such as mucormycosis.

Prior prophylaxis can provide clues to etiology. If a patient with suspected invasive fungal infection has been receiving voriconazole, zygomycosis is a strong possibility. If the patient has not been receiving sulfa-based prophylaxis for Pneumocystis, they are more at risk for Nocardia, Toxoplasma and Listeria as well, although these infections can occur in patients receiving sulfa-based prophylaxis. If a patient is not receiving an acyclovir or ganciclovir derivative, they are at higher risk for HSV and VZV infection.

The CSF formula can be helpful with regards to the possible etiologies of meningitis or meningoencephalitis. Large numbers of CSF WBC (> 500) with neutrophil predominance, low glucose and elevated protein are usually features of bacterial meningitis, whereas viral infections typically have fewer WBC with a lymphocytic predominance and more normal protein and glucose. HHV-6 meningitis may have little or no CSF pleocytosis but may show a positive CSF PCR for HHV-6. Fungal (e.g., cryptococcal) or mycobacterial (e.g., tuberculous) meningitis also may have very low CSF glucose and elevated protein with a variable number of WBC in the CSF. Cryptococcal meningitis with few WBC in the CSF may be the sign of a weak immune response.

With regards to sino-orbital processes, the combination of clinical examination and radiographic appearance is most helpful. Proptosis, chemosis, periorbital edema and limitation of extra-ocular movements may be indicative of progressive space-occupying disease in the sino-orbital area and warrant emergent evaluation by ENT, ophthalmology, and/or neurosurgery. Emergent debridement with stains and cultures can be life-saving in the patient with suspected invasive fungal sino-orbital infection or rhinocerebral mucormycosis or aspergillosis.

Radiography of the brain parenchyma can also be helpful in distinguishing etiologies. Multiple ring-enhancing lesions suggest toxoplasmosis or brain abscesses but may also represent lymphoma or other neoplasms. Infarcts or hemorrhage may be noninfectious but can also be a sign of vasculotropic fungal infections such as aspergillosis. Characteristic white matter lesions can help to diagnose progressive multifocal leukoencephalopathy (PML) but a PCR positive for JC virus in the CSF is a helpful confirmation for that infection. Limbic encephalitis with hippocampal changes can be seen with human herpesvirus-6.

Brainstem lesions (rhomboencephalitis) can be seen with Listeria, HSV or HHV-6 infection, as well as others. Listeria rhomboencephalitis is accompanied by positive cultures in only about 50% of cases, and should be treated with inclusion of high-dose intravenous ampicillin in the regimen whenever this clinical entity is suspected on the basis of clinical and radiographic presentation.

Malignant external otitis is suspected in the diabetic or immunocompromised patient with ear pain and/or drainage with marked systemic toxicity, lethargy, or mental status changes, or signs of temporal bone osteomyelitis and inflammation at the base of the brain. This is an ENT emergency as it can be rapidly progressive. The organism is frequently, though not always, Pseudomonas; antimicrobial resistance is increasingly frequent so it should not be assumed that ciprofloxacin will be effective.

Meningoencephalitis in the setting of disseminated zoster is readily suspected when cutaneous lesions are present, but can be a very difficult diagnosis in the absence of cutaneous zoster lesions.

In addition to infections as described above, noninfectious etiologies can present with mental status changes and/or neurologic signs. Many medications can produce mental status changes; among anti-infectives, some of the most common offenders include carbapenems (e.g., imipenem), quinolones (especially in the elderly or those with renal failure), voriconazole (hallucinations), high-dose acyclovir, and, rarely, ganciclovir.

Toxicity due to calcineurin inhibitors (cyclosporine and tacrolimus) is one of the most common causes of mental status changes in the transplant recipient and should always be considered. These phenomena may occur with high or occasionally with normal levels of these drugs. Calcineurin inhibitors can cause tremors, myoclonus, confusion, seizures, lethargy and unresponsiveness. Characteristic white matter changes may be present on MRI ("posterior reversible encephalopathy syndrome" or "PRES"), with rapid reversibility of these radiographic changes being both a hallmark and a potential diagnostic point.

On the other hand, calcineurin inhibitor toxicity can last clinically for weeks after discontinuation of the agent. Other manifestations of thrombotic microangiopathy (red cell fragments on peripheral blood smear, thrombocytopenia) may or may not be present.

In patients with underlying malignancies, brain metastases and/or carcinomatous or lymphomatous meningitis may mimic CNS infection. CSF cytology is most helpful for the latter, if it can be safely obtained.

Confirmatory tests

With any suspected head and neck or CNS infection, microbiologic diagnosis with culture and susceptibility testing (or PCR for viral etiologies) is crucial. Empiric coverage for a wide range of pathogens is frequently necessary, and leads to toxicity. Even if histopathology is available showing an organism (e.g., fungal hyphae), microbiologic confirmation is very important since different antifungals may be necessary (e.g., for Mucor and other zygomycetes, voriconazole is ineffective and either liposomal amphotericin or posaconazole is necessary.)

4. Specific Treatment

Drugs and dosages

Therapy for suspected bacterial meningitis in an immunocompromised patient often consists of vancomycin, a third-generation cephalosporin, and ampicillin. This combination covers pneumococci, meningococci, and Hemophilus influenzae. (Ampicillin is included for coverage of Listeria, which is a common cause of meningitis in immunocompromised patients.)

If HSV or VZV meningitis or meningo-encephalitis is suspected, high-dose IV acyclovir should be used (10 mg/kg IV Q8h, adjusted for renal function). If CMV meningitis or meningo-encephalitis is suspected, IV ganciclovir should be used.

If cryptococcal meningitis is suspected, initial therapy with a liposomal amphotericin preparation is recommended (plus flucytosine if possible), followed later by a maintenance/suppressive regimen with fluconazole. Increased intracranial pressure should be vigorously treated. Use of liposomal amphotericin rather than standard amphotericin B has been associated with better outcomes in a multicenter retrospective cohort of SOT recipients.

If Zygomycetes (Mucor or Rhizopus) is suspected, in conjunction with surgical debridement, high-dose liposomal amphotericin or posaconazole should be used. For aspergillosis, voriconazole is considered the drug of choice in most clinical settings, with lipid amphotericin preparations and isavuconazole as alternatives. Posaconazole has activity against Aspergillus species but is more useful in prophylaxis. For immunocompromised patients with clinically severe aspergillosis, an echinocandin may be combined with voriconazole for the first 14 days, followed by voriconazole alone, based on a randomized trial of > 400 patients with hematologic malignancies by Marr et al.

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 of 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.

  • Aztreonam 1-2 g IV Q6-8h.

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

  • Cefazolin 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 - 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 of 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 500-750 mg IV Q24h.

  • Linezolid 600 mg IV Q12h.

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

  • 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 a feeding 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.

  • Ticarcillin-clavulanate 3.1 grams IV Q4h.

  • 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 of 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. 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 calcineurin inhibitor toxicity, discontinuation of cyclosporine or tacrolimus is crucial, but may not resolve the syndrome immediately since the drug does not leave the system for some days. Sometimes clinicians switch from one calcineurin inhibitor to another or to sirolimus, but similar toxicity may occur.

For patients with or without a defined etiology of meningitis or meningoencephalitis who have persistent mental status changes, a repeat LP can be very helpful in determining the direction of progress. If quantitative measures are available for the infecting organism (e.g., cryptococcal antigen titer, or quantitative viral PCR for CMV) in the CSF, this information is helpful.

For nonresolving HSV, VZV, CMV meningitis or meningoencephalitis, antiviral resistance is an increasing consideration. If the patient has a rising CMV blood PCR despite therapy with ganciclovir, resistance genotyping should be sent to assess for UL97 and UL54 ganciclovir resistance mutations. Testing for antiviral resistance for HSV and VZV is more difficult to obtain and may require special arrangements with a reference laboratory.

Occasional unusual cases of donor-derived pathogens, such as rabies, lymphocytic choriomeningitis virus and amebic encephalitis due to Balamuthia mandrillaris have been reported. If a donor-derived infection is suspected, the Disease Transmission Advisory Committee of the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) should be notified. Because of these cases, individuals with encephalitis of unknown cause are currently not recommended for use as solid-organ transplant donors.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

In general, resolution of CNS signs and symptoms in the immunocompromised patient may be slow, even with appropriate therapy. Gradual improvement of alertness is anticipated over several days, but may take a week or more, sometimes much longer; however, worsening of mental status or development of new neurologic findings should be investigated urgently.

Occasionally, reduction of immunosuppression and administration of antimicrobial therapy (usually in a fungal infection such as cryptococcosis, histoplasmosis or aspergillosis) may produce an immune reconstitution inflammatory syndrome (IRIS). This phenomenon occurs when apparent clinical worsening of signs and symptoms is accompanied by paradoxical improvement in cultures and other microbiologic parameters. This is thought to be the result of rapidly improving immune competence and immune response against the pathogen in question, and sometimes requires steroid therapy in addition to ongoing antimicrobial therapy.

Incorrect diagnosis

If the patient's mental status and/or neurologic status continues to worsen, or if radiographically new lesions or worsening CSF formula appear, the possibility of a different diagnosis or more than one diagnosis should be considered. Dual diagnoses are common in immunocompromised patients.

If fungal and viral pathogens were not originally sought or covered (i.e. if therapy was given only for suspected bacterial infection), repeat diagnostics with appropriate PCR's and antigen testing (see above) should be pursued.

Follow-up

For patients with CNS lesions on brain imaging, repeat imaging after 4-6 weeks can serve as a guide to the duration of therapy.

Repeat LP is important in cryptococcal meningitis, and may also be pursued in other meningeal infections, particularly if improvement is slow or not measurable.

For patients with CMV or HHV-6 in the CNS, blood CMV and HHV-6 quantitative PCR levels should be followed serially.

Pathophysiology

HSCT recipients are at risk for different types of infections in the three different time periods after transplant. During the pre-engraftment or neutropenic phase, the lack of polymorphonuclear leukocytes to defend against pathogens predisposes to bacterial and fungal infections. During the early post-engraftment phase, when most acute GVHD occurs, patients are highly immunosuppressed (particularly if they develop GVHD) and are at risk for a variety of infections including viral infections such as CMV and VZV.

Prophylaxis and monitoring can alter this risk pattern. The third, or late period, is a time when chronic GVHD can occur, taking the form of skin and eye changes and sometimes bronchiolitis obliterans. Pneumococcal infections are a particular risk during the late time period, and international guidelines for reimmunization (which include pneumococcal conjugate vaccine) should be followed. Pneumococcal infections are more common after allogeneic than autologous HSCT.

Solid organ transplant recipients are less frequently subject to sino-orbital or rhinocerebral invasive fungal infections than are neutropenic HSCT patients, but these infections may occur particularly in the setting of recent therapy for rejection, uncontrolled diabetes and renal dysfunction. Viral infections of the CNS occur in particularly immunosuppressed patients, or those who are not receiving antiviral prophylaxis at times of increased immunosuppression.

Bacterial infections such as Listeria and Pneumococcus relate to community exposures (foodborne in the case of Listeria). Pneumococcal vaccination pre-transplant should help prevent invasive pneumococcal infection; repeating the pneumococcal vaccine 5 years after initial receipt is recommended, and in addition, a dose of 13-valent conjugated pneumococcal vaccine is now recommended for all transplant recipients.

Hypogammaglobulinemia can occur after either HSCT or SOT and can predispose to infections, particularly with encapsulated organisms such as Pneumococcus. Patients with severe or recurrent CNS infections should be screened with a total IgG level, and replacement with IVIg should be considered, particularly if the IgG level is less than 400 mg/dl.

Epidemiology

For either HSCT or solid organ transplant recipients, exposure to fungal spores through gardening, farming, landscaping, marijuana smoking, contact with birds, construction or other outdoor activities increases the risk for invasive fungal infections. Pre-existing sinus colonization may become invasive sino-orbital infection when neutropenia or increased immunosuppression occurs.

Among hematopoietic cell transplant recipients, those who receive cord blood transplants (as opposed to bone marrow or peripheral stem cell transplants) are at higher risk of HHV-6 infection. Receiving more than 1 cord blood transplant confers an even higher risk of HHV-6.

Viral infections such as CMV and HHV-6 can worsen neutropenia and can adversely affect engraftment of HSCT recipients, leading to risk for secondary fungal infections in the setting of a pre-existing viral infection.

Prognosis

Prognosis depends on the particular CNS pathogen and the global and specific immune function of the transplant recipient. In general, resolution of neutropenia, if present, is correlated with a better outcome (use of hematopoietic growth factors such as filgrastim can be important.)

Non-engraftment is an adverse prognostic factor in an HSCT recipient with a severe infection. Reduction of immunosuppression is generally viewed as part of therapy for these infections, but watch for IRIS or immune reconstitution inflammatory syndrome in a small subset of patients in whom immunosuppression is reduced.

For cryptococcal infection, better outcomes are correlated with use of liposomal amphotericin preparations rather than standard amphotericin B. Mortality correlates with renal failure at baseline, and fungemia. Of solid organ transplant recipients with cryptococcosis, those with high cryptococcal antigen titers, fungemia and late-onset disease were more likely to have CNS involvement even in the presence of normal mental status.

About 1/4 of SOT recipients with cryptococcal meningitis have radiographically evident CNS lesions (meningeal, parenchymal, hydrocephalus); parenchymal lesions portend a worse outcome.

For aspergillosis, use of voriconazole (alone or in combination with another antifungal) is associated with better outcomes than amphotericin preparations. Earlier literature showing a dismal prognosis has been altered in the era of mold-active azoles, with more recent results indicating better survival for aspergillosis, although other mold infections still have a high mortality.

Special considerations for nursing and allied health professionals.

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What's the evidence?

Fungal CNS infections

Neofytos, D, Fishman, JA, Horn, D. "Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients". Transpl Infect Dis. vol. 12. 2010. pp. 220-9.

(Excellent review of a complex topic.)

Osawa, R, Alexander, BD, Lortholary, O. "Identifying predictors of central nervous system disease in solid organ transplant recipients with cryptococcosis". Transplantation. vol. 89. 2010. pp. 69-74.

(One of a series of articles based on a large multicenter registry of cryptococcosis in SOT, which has provided new insights into risk factors and management.)

Perfect, JR, Dismukes, WE, Dromer, F. "Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America". Clin Infect Dis. vol. 50. 2010. pp. 291-322.

(Most recent guidelines in general for cryptococcosis management.)

Pongas, GN, Lewis, R, Samonis, G, Kontoyiannis, DP.. "Voriconazole-associated zygomycosis: a significant consequent of evolving antifungal prophylaxis and immunosuppression practices?". Clin Microbiol Infect. vol. 15. 2009. pp. 93-7.

(Exploration of the concern that widespread use of voriconazole might potentially select for fungi not covered by voriconazole.)

Singh, N, Lortholary, O, Dromer, F. "Central nervous system cryptococcosis in solid organ transplant recipients: clinical relevance of abnormal neuroimaging findings". Transplantation. vol. 86. 2008. pp. 647-51.

(As with Osawa et al above, one of a helpful series of studies from a multicenter cryptococcosis - SOT registry.)

Singh, N, Perfect, JR.. "Immune reconstitution syndrome associated with opportunistic mycoses". Lancet Infect Dis. vol. 7. 2007. pp. 395-401.

(Clinically helpful description of this important and recently recognized phenomenon.)

Sun, HY, Alexander, BD, Lortholary, O. "Lipid formulations of amphotericin B significantly improve outcome in solid organ transplant recipients with central nervous system cryptococcosis". Clin Infect Dis. vol. 49. 2009. pp. 1721-8.

(Retrospective multicenter comparison of outcomes of treatment with liposomal vs. standard formulations of amphotericin B.)

Torre-Cisneros, J, Lopez, OL, Kusne, S. "CNS aspergillosis in organ transplantation: a clinicopathological study". J Neurol Neurosurg Psychiatry. vol. 56. 1993. pp. 188-93.

(Correlations of clinical presentations with neuropathology in SOT recipients with various forms of CNS aspergillosis.)

Antifungal Therapy In General

Marr, KA, Schlamm, HT, Herbrecht, R. "Combination antifungal therapy for invasive aspergillosis; a randomized trial". Ann Intern Med. vol. 162. 2015. pp. 81-89.

(Randomized trial of 454 patients with hematologic malignancies and invasive aspergillosis, in which combination therapy with voriconazole plus anidulofungin was associated with improved 6-week mortality compared with voriconazole alone, in the subgroup diagnosed on the basis of galactomannan positivity. Based on this trial, some clinicians use initial combination therapy with voriconazole plus an echinocandin, followed by voriconazole alone, for severe aspergillosis.)

Patterson, TF, Thompson, GR, Denning, DW. "Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America". Clin Infect Dis. 2016.

(Contains important updates; voriconazole remains the drug of choice for invasive aspergillosis, with alternatives being lipid formulations of amphotericin, and isavuconazole.)

Viral CNS infections

Fukuno, K, Tomonari, A, Takahashi, S. "Varicella-zoster virus encephalitis in a patient undergoing unrelated cord blood transplantation for myelodysplastic syndrome - overt leukemia". Int J Hematol. vol. 84. 2006. pp. 79-82.

(Case report of delayed development of VZV encephalitis after resolution of dermatomal zoster in a cord transplant recipient.)

Leveque, N, Galambrun, C, Najioullah, F. "Two cases of varicella zoster virus meningitis found in pediatric patients after bone marrow transplantation despite valaciclovir prophylaxis and without skin lesions". J Med Virol. vol. 78. 2006. pp. 514-6.

(This article discusses the importance of clinical suspicion of CNS VZV and obtaining CSF PCR in immunocompromised patients, even those without skin rash and who are on antiviral prophylaxis.)

Mori, Y, Miyamoto, T, Nagafuji, K. "High incidence of human herpes virus 6-associated encephalitis/myelitis following a second unrelated cord blood transplantation". Biol Blood Marrow Transplant. vol. 16. 2010. pp. 1596-602.

(The association of HHV-6 with HSCT is known but this report provides additional insights into a particularly immunocompromised group of patients.)

Ravindra, KV, Freifeld, AG, Kalil, AC. "West Nile virus-associated encephalitis in recipients of renal and pancreas transplants: case series and literature review". Clin Infect Dis. vol. 38. 2004. pp. 1257-60.

(Helpful case series on the enhanced risk of neurologic involvement in SOT recipients with West Nile virus infection.)

Wainwright, MS, Martin, PL, Morse, RP. "Human herpesvirus 6 limbic encephalitis after stem cell transplantation". Ann Neurol. vol. 50. 2001. pp. 612-9.

(An unusual form of HHV-6 infection after HSCT.)

Other CNS infections

Engelhard, D, Cordonnier, C, Shaw, PJ. "Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey". Br J Haematol. vol. 117. 2002. pp. 444-50.

(An important pathogen in HSCT which should not be neglected.)

Matsuo, Y, Takeishi, S, Miyamoto, T. "Toxoplasmosis encephalitis following severe graft-vs-host disease after allogeneic hematopoietic stem cell transplantation: 17 yr experience in Fukuoka BMT group". Eur J Haematol. vol. 79. 2007. pp. 317-21.

(Another easily missed pathogen that can have a severe neurologic presentation in immunocompromised patients.)

Mizuno, S, Zendejas, IR, Reed, AI. "Listeria monocytogenes following orthotopic liver transplantation: central nervous system involvement and review of the literature". World J Gastroenterol. vol. 13. 2007. pp. 4391-3.

(Early post-transplant Listeria infection mimicking tacrolimus toxicity.)

"Balamuthia mandrillaris transmitted through organ transplantation - Mississippi, 2009". MMWR Morb Mortal Wkly Rep. vol. 59. 2010. pp. 1165-70.

(An emerging pathogen that clinicians should be aware of.)

Noninfectious processes

Adair, JC, Woodley, SL, O'Connell, JB, Call, GK, Baringer, JR.. "Aseptic meningitis following cardiac transplantation: clinical characteristics and relationship to immunosuppressive regimen". Neurology. vol. 41. 1991. pp. 249-52.

(An important item in the differential diagnosis, particularly in patients receiving antilymphocyte therapies.)

Dzudie, A, Boissonat, P, Roussoulieres, A. "Cyclosporine-related posterior reversible encephalopathy syndrome after heart transplantation: should we withdraw or reduce cyclosporine? Case reports". Transplant Proc. vol. 41. 2009. pp. 716-20.

(Calcineurin inhibitors - cyclosporine and tacrolimus - can cause a wide variety of CNS symptoms that can mimic infection and vice versa.)
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