The definition of immune compromise is characterized by an impairment of a host’s ability to effectively handle infectious challenges. As new therapeutic options for previously untreatable illnesses become available, a growing number of children fall into this category. This chapter focuses primarily on the infection-related issues among children who are immunocompromised owing to solid organ or hematopoietic cell transplantation; splenic dysfunction will also be addressed. These special hosts may present for the evaluation of unexplained fever, or with focal signs of infection, and often require a different approach than pursued in an otherwise healthy child. The goal of this chapter is to provide the pediatric hospitalist with a framework for infectious diseases evaluation in these children. Infectious complications related to chemotherapy for malignancy are discussed in Chapter 133.

PATHOPHYSIOLOGY

Solid organ transplantation (SOT) was revolutionized in the early 1980s with the introduction of the immunosuppressant cyclosporine. Heart, kidney, liver, lung, and small bowel transplants have become acceptable therapies for end-organ disease. Although these procedures allow improved survival, infectious complications are among the leading causes of morbidity and mortality in the SOT population.¹ While the surgical procedure itself carries risk of infection following SOT, the immunosuppressive medications used to avoid graft rejection pose significantly higher and more prolonged infectious risks for transplant recipients. The underlying medical conditions necessitating SOT also carry infectious risks that need to be considered. Patients with cystic fibrosis, for example, are colonized with pathogens in their sinuses and upper respiratory tracts which are not impacted by lung transplant. Patients with renal or liver failure, meanwhile, may be predisposed to infection prior to transplant owing to end-organ dysfunction.

Hematopoietic cell transplantation (HCT), which includes transplantation of marrow- or blood-derived stem cells derived from peripheral blood, umbilical cord blood, or bone marrow, treat certain malignancies, metabolic disorders, and immune dysfunctions. Advances in immunosuppression have dramatically improved survival in HCT, but have led to an increased risk of infectious complications. Despite preventive antimicrobial therapies, infection is a leading cause of morbidity and mortality in both autologous and allogeneic HCT recipients.

There are several important variables when evaluating transplant recipients with suspected infection: the type of transplant (type of organ; allogeneic vs. autologous HCT), the amount of time since transplantation (state of immunosuppression), the underlying disease (indication for transplantation), and the environment of the recipient. In solid organ transplantation, the type of organ transplanted confers different technical challenges. Understanding the basic anatomical considerations of organ transplantation facilitates diagnosis and guides empiric antimicrobial therapy during postoperative infections. In HCT, autologous transplants (cells derived from the patient) affords lower risk of infection than use of allogeneic, or donor-derived, cells. As will be discussed below under Differential Diagnosis, the time since transplantation is a critical component to assessing risk of infection in transplant recipients. The degree of immunosuppression varies over time and with it the risk for reactivation of old and acquisition of new infections. HCT patients also deserve particular attention with regard to the stages of engraftment. Neutropenia, defects in cell-mediated immunity and altered antibody-mediated immunity occur at predictable times in HCT patients. Finally, it is important to consider the physical setting of the transplant recipient when assessing for infection. The management will differ according to the risk for community- and hospital-acquired infections based on the environment of the patient prior to evaluation. Each institution carries its own set of nosocomial pathogens and knowledge of local antibiograms is crucial when determining appropriate empiric antimicrobial therapy in immunocompromised hosts. Meanwhile, transplant recipients who have been home are at risk for community-acquired infections, making it important to be aware of seasonal infections and community outbreaks. Further, regional infections (e.g. histoplasmosis, blastomycosis, coccidioidomycosis, strongyloides) should be considered; a detailed travel history should be obtained.

Other considerations include the patient’s age, preoperative risk factors such as malnutrition, donor and recipient serostatus for Epstein-Barr virus (EBV) and cytomegalovirus (CMV), intraoperative complications, and the specific postoperative immunosuppressive regimen.

The time from transplantation is a key factor that influences infection risk following transplant. For both HCT and SOT recipients, the time period between transplantation and evaluation influences the differential diagnosis for suspected infection. Prior to implementation of prophylactic and preventive antimicrobials, certain infections in the post-transplant period followed a predictable pattern that allowed for prioritized evaluation and empiric treatment. Figure 109-1 depicts the classic timetable for the development of infections after SOT and HCT. Some of the listed infections, such as CMV and HSV, have shifted their timeframes to develop later after transplant due to common use of prophylaxis or preventive antimicrobials.

EARLY POST-TRANSPLANT PERIOD

Solid Organ Transplantation (0–30 Days)

Immediately after transplantation, bacterial pathogens predominate as the cause of infection. In SOT recipients, the source of bacterial infection is typically related to the surgical procedure performed or the presence of an indwelling device (e.g. catheter, drain, stent).² Although immunosuppression is implemented during this period, most infections are directly related to surgery and peri- and postoperative care. For example, peritonitis is the principal postoperative infection in liver transplant recipients, whereas urinary tract infections are common following renal transplantation. Infection can be also be conveyed with the allograft (donor-derived infections) or reactivation of an infection present at surgery can resurface, although these occur less frequently.³

Fungal infections, predominantly caused by Candida species, also occur early after solid organ transplantation. Factors predisposing to fungal infection include disruption of anatomic barriers by surgery, fungal colonization enhanced by broad-spectrum antibiotic therapy, and presence of indwelling catheters. The incidence varies by type of organ transplanted; lung and liver transplants involve a higher incidence of fungal infection than do kidney transplants. Particularly problematic is fungal pneumonia after lung transplantation, because colonization is frequent and difficult to distinguish from infection.⁴ Infections caused by Aspergillus species, although less common than Candida spp. infections, are associated with high mortality.

Hematopoietic Cell Transplantation—Pre-Engraftment (First 15–45 Days)

For HCT recipients, the pre-engraftment period begins with conditioning therapy that eradicates or reduces the patient’s burden of abnormal or malignant cells to below detectable levels and suppresses the patient’s immunity to prevent the rejection of donor cells. This period, which extends until approximately 15 to 5 days after transplantation, is complicated by neutropenia, lymphopenia, and mucositis. Patients react similarly to those with neutropenia from other forms of chemotherapy. Bacterial and fungal infections commonly can gain entry through indwelling venous catheters or through mucosal breakdown along the gastrointestinal tract. If initial conditioning therapy includes agents directed at T cells, the patient is predisposed to an earlier onset of viral infection, particularly EBV, CMV, adenovirus, and BK virus. Reactivation of herpes simplex virus (HSV) may also occur, making antiviral prophylaxis part of standard therapy during the pre-engraftment period.⁵

INTERMEDIATE POST-TRANSPLANT PERIOD

Solid Organ Transplantation (1–6 Months)

Between 30 and 180 days post-transplantation, viral causes of infection predominate.^6,7 During this time, opportunistic infections and post-transplant lymphoproliferative disorder (PTLD) must also be considered. The type of organ transplanted influences the risk of specific infections. For example, bacterial and fungal pneumonia are common in lung transplant patients and recurrent bacterial cholangitis occurs in liver transplant patients with biliary strictures and drains. However, CMV, EBV, adenovirus, varicella-zoster virus (VZV), and the childhood respiratory viruses must be considered in all SOT patients with fever during this period.

Opportunistic infections are relatively rare following pediatric solid organ transplantation. Because trimethoprim-sulfamethoxazole prophylaxis has been incorporated into treatment regimens, infection with Pneumocystis jirovecii (previously Pneumocystis carinii) has been almost eliminated. Toxoplasma gondii infection should be considered in seronegative heart transplant recipients, especially if the donor was seropositive.

Hematopoietic Cell Transplantation—Post-Engraftment (Marrow Recovery—100 Days)

In HCT patients, the post-engraftment period begins with marrow recovery and extends to 100 days after transplantation, when functional lymphocyte recovery is apparent. This is a time of impaired cellular immunity. Graft-versus-host disease (GVHD) and the use of calcineurin inhibitors, which blunt T-lymphocyte reconstitution via their inhibitory effect on interleukin-2, also play a role in risk for infection. CMV, EBV, and VZV are frequent causes of infection during this time. Bacterial infections from indwelling catheters and fungal infections, both Candida and Aspergillus species, continue to be a problem as well. Other opportunistic infections, such as P. jirovecii, and reactivation of T. gondii may occur during this period.⁵

LATE POST-TRANSPLANT PERIOD

Solid Organ Transplantation (>6 Months)

Late infections, typically occurring 180 days or longer after transplantation, include many of the same viral illnesses that occur in the immunocompetent population (e.g. gastroenteritis, viral respiratory infection). Particular attention should be paid to varicella, influenza, and adenovirus infection, because these can be particularly severe in transplant recipients. EBV-associated PTLDs can also occur during this period. In lung transplant patients, bacterial (including gram-negative bacilli) and fungal pneumonia remains a concern. Additionally, with routine use of ganciclovir and valganciclovir for CMV prophylaxis, late-onset CMV disease (after discontinuation of prophylaxis) is also an important consideration during this period.⁸

Hematopoietic Cell Transplantation—Late Phase (>100 Days)

The late phase begins 101 days after transplantation. Impaired cellular immunity persists and GVHD can become a chronic problem. The risk of infection during this period is directly related to underlying disease state and the need for ongoing immunosuppression. The use of prophylactic antimicrobials may shift reactivation of certain infections, such as CMV, VZV, and HSV, to this period. The presence of chronic GVHD predisposes to EBV-related complications as well as to late-onset infections with encapsulated organisms, particularly pneumococci. The risk for community-acquired infections is greatest during this period as patients’ care is transitioned to the outpatient setting.

SPECIFIC INFECTIONS FOLLOWING TRANSPLANTATION

Bacterial Infections

Infections are common immediately after liver transplantation, and most are associated with either central venous line or abdominal infections. Factors predisposing to infection include previous abdominal surgery, prolonged operating time, hepatic artery thrombosis, and biliary strictures. Prolonged operating time and repeated surgical procedures increase the risk for bowel perforation and subsequent infection with Enterococcus species or gram-negative bacilli.⁸ Biliary strictures and hepatic artery thrombosis predispose to cholangitis and hepatic abscesses with similar organisms.⁹ Postoperative cholangitis is particularly difficult to differentiate from acute cellular rejection, and a biopsy is often warranted to help choose the appropriate therapy.

Postoperative bacterial infections in renal transplant patients are similar to those of any postoperative patient and include pneumonia, wound infection, central venous catheter infection, and urinary tract infection. However, uncomplicated urinary tract infection, pyelonephritis, and urosepsis all occur with increased frequency in this population.⁶ Historically, one third of renal transplant patients developed recurrent urinary tract infections in the first 6 months after transplantation, but this number is now lower with increased use of prophylactic antibiotics.

Blood and pulmonary infections are the most common bacterial infections in heart transplant recipients.¹⁰ Staphylococcus aureus is the organism most likely to cause mediastinitis.¹¹ Surgical re-exploration of the wound is critical for successful treatment. Infants less than 6 months of age appear to have a higher risk of bacterial infection than older pediatric heart transplant recipients.

Bacterial pneumonias following lung transplantation occur in the majority of patients. Cystic fibrosis patients have a challenging microbial ecosystem which is not eliminated by transplantation. Gram-negative bacilli, Staphylococcus aureus, and atypical mycobacterial pathogens are common following lung transplant in cystic fibrosis patients and multidrug resistance should be expected.¹² Pre-transplant colonization with Burkholderia cepacia complex (B. cenocepacia) portends a lower survival following transplant.¹³ Bloodstream infections are also frequent following lung transplantation, primarily due to the presence of central venous catheters, and complicate more than a quarter of postoperative lung transplantation courses.¹⁴

Bacteremia and serious bacterial infections caused by gram-positive organisms are common after HCT. Mucositis and indwelling catheters in the pre-engraftment period and chronic GVHD in the late phase predispose to such infections. Mucositis and indwelling catheters predispose to infections with Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus viridans, Streptococcus pyogenes, and Enterococcus species. S. viridans is particularly important, being isolated from approximately 15% of adult transplant patients with mucositis and neutropenia in the weeks following transplant. It can present with fever alone or with overwhelming sepsis.¹⁵ Viridans group streptococci usually gain access to the bloodstream via mucositis and can cause a sepsis syndrome with multiorgan dysfunction in the early pre-engraftment period.¹⁶ Infection with S. pneumoniae continues to be a problem in patients with chronic GVHD despite the use of prophylactic penicillin or trimethoprim-sulfamethoxazole in many centers.¹⁷ Gram-negative organisms can present with a more fulminant, devastating course.

Clostridium difficile should be considered in any transplant patient with diarrhea, especially if prolonged or severe. Exposure to antibiotics and immunosuppressives following transplantation increase the likelihood of disease and of complications. The peak onset is in the first 1 to 2 weeks following SOT.¹⁸ In HCT recipients, C. difficile may also predispose patients to GHVD and severe infection is associated with decreased overall survival.¹⁹

Viral Infections

Unlike bacterial infections, viral infections tend to have lower organ specificity because they are usually related to chronic immunosuppression. Transmission can occur through reactivation of a latent virus, transmission via the transplanted organ, or person-to-person spread in the hospital or in the community. The herpesviruses are a major source of post-transplant morbidity and mortality, especially CMV, EBV, HSV, and VZV. Other important viral infections in solid organ transplant patients include adenovirus, parvovirus, influenza virus, parainfluenza virus, and respiratory syncytial virus (RSV).

Cytomegalovirus (CMV)

Despite various preventive regimens with antiviral agents and CMV-specific immune globulin, CMV remains a common cause of morbidity in the transplant population. Primary infection after SOT, whereby a CMV-naïve (seronegative, R-) recipient receives an organ or blood products from a CMV-infected (seropositive, D+) donor, is the most severe. Primary infection can also occur in a D-/R- patient due to nosocomial or community exposures. HCT recipients can acquire CMV through receipt of blood products, including stem cells, from CMV-seropositive donors or via hospital or community exposures. The use of CMV-safe blood products is recommended. HCT recipients at risk for CMV disease include those that are CMV-seropositive prior to transplant and all who are CMV-seronegative that have a CMV-seropositive donor. Primary infection occurs more frequently in children than in adults because a greater proportion of children are CMV naïve at the time of transplant. Reactivation of a previously acquired (latent) CMV infection or infection with a different strain of CMV usually results in less severe disease.⁷ In addition to CMV naïveté, high doses of immune suppression (especially antilymphocyte therapy used for rejection) and EBV co-infection (due to the immune-modulating effects of EBV) increase the risk for CMV disease.

CMV infection can present as a nonspecific viral syndrome, termed CMV syndrome, or it can present with end-organ involvement. CMV syndrome usually involves several of the following symptoms: fever, malaise, weakness, myalgia, and arthralgia. There is often an accompanying myelosuppression. End-organ CMV disease often affects the transplanted organ, with hepatitis in liver transplant patients²⁰ and pneumonitis in lung transplant patients being the most common associations. The gastrointestinal tract can be affected regardless of the organ transplanted, and lower gastrointestinal bleeding in a transplant patient should raise the suspicion of CMV colitis.

CMV is a significant cause of morbidity and mortality in HCT recipients as well. Pre-transplant exposure with documented CMV immunoglobulin G levels is a risk factor for recurrence after transplantation due to reactivation of latent disease. End-organ disease from CMV can include pneumonitis, hepatitis, enteritis, and retinitis. Even with improved preventive strategies, CMV continues to be the most worrisome viral pathogen in transplant centers. As in solid organ transplants, the immune-modulating properties of CMV link it to graft rejection. More unique to HCT, however, is its occurrence in conjunction with GVHD.

Diagnosis of CMV disease has changed in the past decade. CMV serology still plays an important role for risk stratification prior to transplantation in both SOT and HCT but does not have a role in diagnosis of active infection. Quantitative real-time polymerase chain reaction assay (QRT-PCR) is now the most frequently implemented tool for diagnosis and surveillance post-transplantation.

Diagnosis of CMV infection and disease must take current prevention strategies into account for a given patient. Pre-emptive antiviral therapy, which involves initiation of therapy when infection meets a predefined threshold based on elevated CMV DNA viral loads, is now being initiated at many centers in low-risk patients.²¹ This differs from prophylaxis, which consists of empiric therapy and aims to prevent development or spread of infection. For both prevention and treatment, the drug of choice for CMV is ganciclovir, which inhibits CMV DNA polymerase. An oral form, valganciclovir, is now available and is being used increasingly in pediatric transplant patients with mild or no symptoms in the face of stable CMV DNAemia.²²

Epstein-Barr Virus (EBV)

Primary infection from an infected donor to a naïve recipient represents the most common and severe form of EBV infection in SOT recipients. Children are particularly prone to infection owing to the relatively high incidence of EBV-naïve recipients. Clinical manifestations of primary infection include enteritis, hepatitis, encephalitis, and mononucleosis-like symptoms including fever, hepatosplenomegaly, and lymphadenopathy.²³ EBV disease in HCT is most often from reactivation of endogenous infection or transmission due to receipt of a graft from an EBV-seropositive donor. Primary infection due to community contact with an individual with EBV disease is also possible.

Following primary infection, EBV, like other herpesviruses, persists for the lifetime of the host despite the presence of a strong humoral and cell-mediated immune response. Ongoing low-grade viral replication normally occurs in the oropharynx simultaneously with a predominantly latent infection of B cells in the peripheral blood and lymphoid tissues. In cases of severe immunosuppression (e.g. following hematopoietic stem cell or solid organ transplantation), the equilibrium is disrupted in favor of the virus. The uncontrolled proliferation of EBV-infected B cells that occurs in this context may result in a spectrum of post-transplant lymphoproliferative disorders (PTLDs). The spectrum of PTLDs ranges from self-limited polyclonal proliferation to true malignancies containing clonal chromosomal abnormalities.²⁴

Factors associated with increased risk for PTLD include younger patient age, intestinal or multivisceral transplants,²⁵ antigenic differences between donor and recipient, more intense immune suppression, and co-infection with other pathogens. T-cell lymphopenia is a strong predictor of PTLD in HCT recipients. The cumulative intensity of immunosuppression also increases the risk of PTLD. The specificity of calcineurin inhibitors and antilymphocyte antibodies for the T-cell limb of the immune response may explain in part the higher frequency of PTLD associated with the use of these agents. Co-infection with other herpesviruses such as CMV and human herpesvirus-8 also increases the risk of PTLD.

The clinical presentation of PTLD can be variable, ranging from a benign illness with self-limited lymphoproliferation to fulminant disease that presents with localized nodules, multifocal disease, or a sepsis-like picture. The most common presentation in children is similar to that of mononucleosis, with vague constitutional symptoms of fever, fatigue, and myalgias accompanied by a sore throat, cervical lymph node hypertrophy, and tonsillar enlargement. Gastrointestinal involvement can present with bleeding, weight loss, constipation, diarrhea, hypoalbuminemia, or intussusception. Pulmonary involvement can present with respiratory distress or lung nodules on the chest radiograph.

Diagnosis is best made by taking a tissue sample of the affected lymph node or tissue. Similar to CMV, nucleic acid PCR for EBV is an invaluable diagnostic tool. Elevated levels can prompt the early adjustment of immune suppression, which may impact development of PTLD.²⁶

Reduction in immune suppression alone is often successful in treating PTLD limited to the allograft. If reduction of immune suppression is ineffective, or if the patient presents with advanced disease, there are other treatment options. Treatment with rituximab, a monoclonal antibody to CD20-positive B cells, can be added.^27,28 Other chemotherapeutic agents, such as cyclophosphamide and infusions of donor-derived EBV-specific cytotoxic T lymphocytes also have a role in individual cases.^29-31

Varicella-Zoster Virus (VZV)

Most children are either exposed to varicella before adolescence or immunized at 1 year of age. Children who receive organs before being either exposed or immunized are at risk for severe varicella infection, although herd immunity and the rapid decline in the incidence of varicella lessen that risk somewhat.

VZV can cause illness as a primary infection or after reactivation of latent virus. Reactivation is much more common and typically occurs several months after transplantation. Patients may have typical painful vesicular lesions in a dermatomal distribution, or the lesions may be atypical with a less obvious pattern. The lesions may also be present for a prolonged period despite appropriate antiviral treatment. Dissemination can occur with primary infection (rarely with reactivation) and can result in significant end-organ disease, including hepatitis and pneumonitis; visceral dissemination does not have to be accompanied by rash.

The most effective means of preventing severe VZV disease is pre-transplant vaccination. Although studies have shown VZV vaccine to be safe and effective following SOT,³² it is not recommended outside of a research setting. Therefore, if a VZV-seronegative, immunosuppressed transplant patient has a significant contact with a VZV-infected person (>5 minutes face-to-face contact, intimate contact, or contact with an immune-compromised individual with VZV), VZV-specific immune globulin (Varizig) should be administered within 96 hours of the exposure.³³ Intravenous immunoglobulin (IVIG) can be used as an alternative if Varizig is unavailable. If clinical disease develops, either primary infection or reactivation (herpes zoster), patients should receive intravenous acyclovir in the hospital.³⁴

Herpes Simplex Virus (HSV)

HSV is the most common viral infection following HCT and often occurs fairly early in the pre-engraftment or conditioning phase. HSV usually presents with oral or perianal vesicular or ulcerative lesions but occasionally progresses to systemic disease with hepatitis or encephalitis. Marked reduction in the incidence of HSV has been achieved with the use of prophylactic acyclovir.³⁵

HSV reactivation appears to be more common in HCT than in solid organ transplant recipients and has led to the universal use of prophylactic acyclovir for all seropositive patients.³⁶ If oral vesicles occur, diagnosis is achieved when HSV is detected by PCR, direct fluorescent antibodies, or viral culture of the vesicle. Dissemination can occur with primary infection and, less commonly, with reactivation and can result in significant end-organ disease, including hepatitis and pneumonitis.

Patients with suspected HSV infection should receive intravenous acyclovir empirically while awaiting diagnostic confirmation.

Adenovirus

Adenovirus is a common cause of infection in all transplant recipients and clinical manifestations may vary.³⁷ As in solid organ transplant recipients, adenovirus can cause significant disease in HCT recipients but seems to be more common in patients with GVHD. Clinical manifestations include hemorrhagic cystitis, pneumonitis, nephritis, gastroenteritis, and hepatitis.

Risk factors for severe infection are similar to those for other viruses and include extremes of age, infection within 1 month of transplantation, and high levels of immunosuppression. Different adenovirus serotypes have a propensity to infect different organs, leading to specific clinical manifestations. For example, liver transplant recipients tend to develop hepatitis or gastroenteritis from serotypes 1, 2, and 5.³⁸ In contrast, lung transplant recipients develop pneumonitis and obliterative bronchiolitis, and renal transplant recipients often develop hemorrhagic cystitis or prolonged urinary tract infections caused by serotypes 11, 34, and 35.

Detection of adenovirus by culture, antigen detection, or PCR suggests infection only in the context of compatible clinical symptoms. Diagnosis of disease can be challenging to distinguish from shedding because patients may shed adenovirus asymptomatically for prolonged periods.³⁹

The role of antiviral agents is unclear. Both IVIG and cidofovir have been used therapeutically, with anecdotal reports of success in severe infections.⁴⁰

Parvovirus

Parvovirus B19 was first recognized as a cause of red cell aplasia in sickle cell patients. It has also been identified as a cause of aplastic anemia and, to a lesser extent, pancytopenia in the transplant population. The aplasia can occur with or without systemic signs of fatigue, malaise, fever, and arthralgias. Parvovirus DNA can be detected by PCR and low-level viremia may persist for several months following initial infection. Testing is indicated in the setting of chronic anemia and treatment is with IVIG, although adjustment in immunosuppression may also be needed.⁴¹

Influenza Virus

Influenza virus has significant morbidity and mortality in both immunocompetent and immunocompromised populations. Morbidity in transplant patients increases with lung transplantation, extremes of age, high levels of immunosuppression, and occurrence of infection immediately post-transplant.⁴² The Centers for Disease Control and Prevention (CDC) has long recommended vaccination before influenza season and chemoprophylaxis during outbreaks for immunocompromised patients.⁴³ If a transplant patient presents with signs and symptoms compatible with influenza, early diagnosis with a rapid antigen assay and empiric treatment with oral antiviral therapy are warranted. Oseltamivir is often used owing to its efficacy against both influenza A and B. Chemoprophylaxis should be offered to all transplant recipients who come in close contact with an individual with suspected or confirmed influenza infection. The CDC maintains the latest information on seasonal influenza activity and sensitivities, providing up-to-date guidance on optimal antiviral treatments (http://www.cdc.gov/flu/professionals/index.htm).

Respiratory Syncytial Virus (RSV)

RSV causes a wide range of symptoms in transplant patients, although upper and lower respiratory tract infections are most common. The risk factors for severe disease are similar to those for influenza: lung transplantation, extremes of age, greater immune suppression, and infection early after transplantation. Unlike influenza, however, there is no proven therapy. Ribavirin could be considered in severe cases.⁴⁴ There are insufficient data to determine whether palivizumab is effective in treating RSV pneumonia in solid organ recipients.

Other Viruses

Human herpesvirus-6 (HHV6) is a common infection following transplantation owing to a high rate of reactivation.⁴⁵ Although the vast majority of patients (99%) are asymptomatic, this virus has been associated with development of numerous clinical symptoms including fever, rash, hepatitis, pneumonitis, graft dysfunction, and neurologic symptoms. Diagnosis is most often made by PCR, but the significance of detection of HHV6 DNA is challenging given the frequency of asymptomatic reactivation.

Parainfluenza viruses (PIV) are common respiratory viruses. Infections generally begin as mild upper respiratory symptoms, but may progress to severe lower respiratory tract infections including giant cell pneumonia. Risk of lower tract disease appears to relate to use of corticosteroids and underlying lymphopenia.⁴⁶ The efficacy of ribavirin has not been established in PIV. DAS181, a novel sialidase fusion protein, shows promise at prevention and treatment of PIV disease, but is available for investigational use only.⁴⁷