Viral Infections

Opportunistic viral infections are a particular problem in cancer patients who undergo HCT and in individuals with hematologic cancers. Accurate diagnosis of viral infections is important, as treatment is available for many of them.

Etiology

As mentioned previously, viral infections in cancer patients are caused predominantly by herpesviruses (HSV, VZV, CMV, HHV-6, and EBV). The herpesvirus infections usually are reactivations of latent infections. CMV, HHV-6, and EBV are mostly encountered in HCT recipients. Respiratory viruses that infect cancer patients include RSV, influenza viruses A and B, parainfluenza virus, rhinovirus, adenovirus, and human metapneumovirus.

Signs and Symptoms

Although all of the herpesviruses can cause fever and a septic picture, HSV usually presents as mucositis or a vesicular rash; VZV presents as a vesicular rash in a dermatomal distribution; and CMV, in the HCT setting, presents as interstitial pneumonia. When HSV or VZV disseminates, each virus can cause disseminated cutaneous lesions or visceral (liver, lung, brain) involvement. VZV infection can present with GI symptoms, such as epigastric or generalized abdominal pain.

Diagnosis

To make a specific viral etiologic diagnosis, tissue or fluid must be obtained from the infected site and processed for histologic/cytologic examination, PCR, and culture.

Vesicular skin lesions

When a cancer patient presents with a vesicular rash, it is invariably due to either HSV or VZV. If the distribution of lesions is in a dermatomal pattern, a clinical diagnosis of VZV can be made. However, if there is cutaneous dissemination, the vesicular lesions should be aspirated (and sent for viral culture/PCR) or scraped down to the base, smeared on a glass slide, and sent for direct fluorescent antibody (DFA) staining (for HSV and VZV).

Visceral involvement

When there is visceral involvement with HSV, VZV, or CMV, biopsy material is examined for inclusions and is submitted for culture.

Respiratory infection

For the respiratory viruses, diagnosis is usually made by examination of nasal/nasopharyngeal washing, bronchoalveolar lavage fluid (obtained by bronchoscopy), or biopsy (obtained by transbronchial, percutaneous thoracic, thoracoscopic, or open lung biopsy). In the special case of CMV interstitial pneumonitis in the HCT setting, diagnosis of infection (prior to disease onset) can be made by detection of antigens or virus in the bloodstream, in addition to evidence of the virus in bronchoalveolar lavage fluid. PCR and DFA are available for various community respiratory viruses (eg, adenovirus, parainfluenza, influenza, RSV, rhinovirus, and metapneumovirus).

CNS involvement

CNS involvement can be determined by PCR performed on the cerebrospinal fluid for the following agents: HSV, VZV, HHV-6, CMV, EBV, and adenovirus.

Antibody testing is of little use in the diagnosis of viral infection in the cancer patient.

Evidence of CMV viremia

Evidence of CMV viremia, which is utilized to initiate preemptive therapy, can be determined by PCR, antigen detection, or blood (shell-vial) culture.

Treatment

HSV infection

Localized HSV infection is usually treated with acyclovir, at 5 mg/kg IV q8h. If there is dissemination, a dose of 10 mg/kg q8h can be used, and if there is CNS involvement, a dose of up to 15 mg/kg IV q8h can be utilized. If acyclovir-resistant HSV is suspected, foscarnet can be used (see Table 1 for doses). However, this is a nephrotoxic drug.

VZV infection

VZV infection is usually treated with acyclovir, administered at a dose of 10 mg/kg IV q8h.

CMV infection

CMV infection is treated with ganciclovir or foscarnet. Ganciclovir is the drug of choice but is toxic to bone marrow.

In the HCT setting, “preemptive” treatment (to prevent disease after evidence of infection is obtained) consists of ganciclovir at 5 mg/kg IV bid for 14 days or until viremia is cleared, whichever is longer, followed by 5 mg/kg/d IV for another 3 to 5 weeks. Actual treatment of CMV interstitial pneumonia consists of ganciclovir at 5 mg/kg IV q12h, along with immunoglobulin at 500 mg/kg IV every other day for 21 days (induction phase). Maintenance therapy consists of ganciclovir at 5 mg/kg/d IV for 5 days each week, and immunoglobulin at 500 mg/kg IV every week.

Foscarnet can be used instead of ganciclovir if there is marrow toxicity, but it poses a potential risk of nephrotoxicity.

For CMV infection resistant to both ganciclovir and foscarnet, cidofovir can be used.

HHV-6

HHV-6 infection/disease can be treated with ganciclovir, foscarnet, or cidofovir.

Respiratory viral infection

Regarding infections with the respiratory viruses, zanamivir and oseltamivir (75 mg PO bid) can be used for both influenza A and B. Rimantadine or amantadine, both 100 mg PO bid, in combination with oseltamivir has been recommended for resistant influenza A dependent on yearly Centers for Disease Control and Prevention (CDC) recommendations. However, since the H1N1 strain has been in circulation, addition of rimantadine or amantadine has not been needed. Clinicians should refer to the CDC for final recommendations anually. Finally, cidofovir has been used (but is not FDA approved) for adenovirus infection.

Prevention

Herpesvirus infections

Acyclovir. HSV and VZV reactivate with great frequency in cancer patients undergoing chemotherapy and/or radiation therapy. This finding is especially true in the HCT population, in which 80% of HSV-seropositive patients and up to 40% of VZV-seropositive patients have a reactivation of HSV or VZV. Therefore, in HSV-seropositive HCT patients, prophylactic acyclovir is indicated. Any HSV infection that occurs during acyclovir prophylaxis should be considered resistant to acyclovir. Acyclovir has also been shown to reduce the incidence of CMV infection after HCT. It is now recommended by some to extend HSV prophylaxis for 1 year or longer for patients with allogeneic HCT or GVHD, that is, those at risk for VZV reactivation. In patients exposed to VZV, acyclovir should be given at a dose of 800 mg (for adults) or 20 mg/kg (for pediatric patients, with a maximum dose of 800 mg) four times daily on days 3 to 22 after exposure.

Ganciclovir. Ganciclovir is generally considered too marrow-toxic to be used as universal prophylaxis against CMV. Thus, the preemptive approach was developed to focus on only treating those who had evidence of CMV infection (viremia) as determined by PCR, antigen detection, or blood (shell-vial) culture. This approach allows treatment of viremia before it evolves into CMV disease (interstitial pneumonitis).

Reduction of CMV infection. In the small group of HCT recipients who are CMV-seronegative, the use of CMV-seronegative blood support has been shown to reduce CMV infection dramatically. In a study by Marty et al, CMX001, an orally bioavailable lipid acyclic nucleoside phosphonate of cidofovir, was reported to significantly reduce CMV events in recipients of hematopoietic stem cells. Further investigations are needed.

Varicella and VZV vaccines. Varicella and VZV vaccines (Varivax) should not be given to patients with hematologic malignancies, malignant neoplasms, or immunodeficiencies. The exception is with varicella vaccine in patients with childhood leukemia in remission for 1 year, when selected criteria are met.

Influenza

Inactivated influenza vaccine. Inactivated influenza vaccine should be administered yearly to all cancer patients, although the efficacy of the influenza vaccine is unknown in the HCT population. Optimal timing of vaccination is not established, but serologic responses may be best between chemotherapy cycles (> 7 days after the last treatment) or > 2 weeks before chemotherapy starts.

Influenza outbreak. Rimantadine, amantadine, zanamivir, or oseltamivir can be given prophylactically during an outbreak of influenza.

Antimicrobial Stewardship

There are a limited number of new antibiotics in the pipeline and a worrysome number of drug-resistant and multidrug-resistant organisms. To preserve the utility of remaining antibiotics, stewardship of antimicrobials is important. The goals of stewardship are to minimize inappropriate use of antimicrobials and development of acquired resistance, improve patient outcomes, reduce toxicity, and decrease costs associated with inappropriate antibiotic use.

Suggested Reading

On Infection During Febrile Neutropenia

Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guidelines for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 52:e56–e93, 2011.

National Comprehensive Cancer Network: Prevention and Treatment of Cancer-related Infections. V.2.2011. Available at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

On Pneumonia

American Thoracic Society; Infectious Diseases Society of America: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171:388–416, 2005.

Mandell LA, Wunderink RG, Anzueto A, et al: Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(suppl 2):S27–S72, 2007.

On Catheter-Associated Infections

Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guidelines for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 52:e56–e93, 2011.

O’Grady NP, Alexander M, Burns LA, et al: Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis 54:1053–1063, 2012.

On C difficile Infections

Alonso CD, Treadway SB, Hanna DB, et al: Epidemiology and outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 54:1053–1063, 2012.

Cohen SH, Gerding DN, Johnson S, et al: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 31:431–455, 2010.

On Fungal Infections

Pappas PG, Kauffman CA, Andes D, et al: Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535, 2009.

Walsh TJ, Anaissie EJ, Denning DW, et al: Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 46:327–360, 2008.

Ito IJ, Kriengkauykiat J, Dadwal SS, et al: Approaches to the early treatment of invasive fungal infection. Leuk Lymphoma 51:1623–1631, 2010.

On Viral Infections

Harper SA, Bradley JS, Englund JA, et al: Seasonal influenza in adults and children—Diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: Clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 48:1003–1032, 2009.

Marty FM, Winston DJ, Rowley SD, et al: CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med 369:1227–1236, 2013.