Infectious Complications

Viral infections

Opportunistic viral infections are a particular problem in cancer patients who undergo HCT and those 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).

Intravenous formulations of currently available antiviral influenza agents are under investigation, including oseltamivir(Drug information on oseltamivir) (Tamiflu) and zanamivir(Drug information on zanamivir) (Relenza). A new antiviral agent, peramivir, is also under investigation for the treatment of influenza. These intraveous formulations may be useful for patients in whom absorption may be unreliable or in those who cannot tolerate oral or inhaled formulations. (For more information, visit clinitaltrials.gov.)

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, 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, 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(Drug information on 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 7 days 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

Among infections with the respiratory viruses, zanamivir and oseltamivir (75 mg PO bid) can be used for both influenza A and B. Rimantadine (Flumadine) or amantadine (Symmetrel), both 100 mg PO bid, in combination with oseltamivir has been recommended for resistant influenza A dependent on yearly CDC recommendations. Finally, cidofovir has been used (but 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, maximum 800 mg/dose) 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).

CMV-seronegative blood support

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.

Varicella and VZV vaccines (Varivax)

Varicella and VZV vaccines (Varivax) should not be given to those 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.

Rimantadine, amantadine, zanamivir, or oseltamivir

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