Management of Respiratory Viral Infections After Hematopoietic Stem Cell Transplantation, Research Paper Example

Abstract

Hematopoietic Stem Cell Transplant (HSCT) is the infusion of hematopoietic stem cells from an individual human donor into a patient who has received chemotherapy.  After HSCT has been performed, there are opportunistic pathogens that can invade the host and cause serious respiratory illness.  Treatment and management for proper immune system recovery in HSCT recipients therefore is extremely necessary and in some cases very specific, particularly for RSV and influenza. In order to prevent serious respiratory illnesses from occurring in HSCT recipients, it is recommended for patients to general safety precautions such as frequent hand washing and sanitizing, and isolation from people with respiratory symptoms or illnesses.

Introduction

Hematopoietic Stem Cell Transplant (HSCT) is the infusion of hematopoietic stem cells from an individual human donor into a patient who has received chemotherapy for disease such as neoplastic diseases, hematologic disorders, enzyme deficiencies, autoimmune diseases, and hematologic disorders (CDC, 2000; Appelbaum, 1996; Sobocinski et al., 1994; Kessinger et al., 1993; Bortin et al., 1992).    In fact, HSCT has become a standard treatment for these types of diseases and disorders (Zittoun et al., 1995; Applebaum, 1996; Thomas et al., 1986).  After HSCT has been performed on a patient, there are predictable immune system deficiencies and recoveries which the recipient undergoes.  The patient is treated with chemotherapy or radiation therapy before receiving the HSCT and therefore causes a series of issues.  The normal routine for chemotherapy also destroys the normal cells such as neutrophils, monocytes, and macrophages, as well as, damages mucosal progenitor cells.  This causes a loss of the mucosal barrier, which in turn leads to problems in the gastrointestinal tract.  The gastrointestinal tract, which normally contains pathogens such as bacteria, fungi, and other bacteria-carrying sources of the skin and mucosa, then becomes a possible home to potential harmful pathogens. (CDC, 2000)  The recipients lose their T- and B-lymphocytes, which affects their immune memory response in which they have created over their lifespan, and although they are receiving donor immunity from the transplant, they are still prone to infectious diseases.

There are opportunistic pathogens that invade the host after HSCT.  From past research, there are specific infections that occur at different times post HSCT.  Therefore, management and immune system recovery in HSCT recipients occurs in three different phases beginning with the first day of the transplant. Phase I is the preengraftment phase which is the first 30 days.  During this phase, recipients are at risk for prolonged neutropenia and breaks in the mucocutaneous, leading to oral, gastro-intestinal and skin infections.  Phase II, the postengraftment phase occurring from 30-100 days after HSCT is governed by impairment in the cell-mediated immunity. The extent of impact during this phase is related to graft-versus-host disease (GVHD) and how the recipient’s body responded to the transplant.  During this phase, the herpes viruses and pneumonia virus’s s infect the recipient causing pneumonia and hepatitis.   Phase III is the late phase occurring 100 days after the transplant.  Patients during this phase have a better immune response; however, patients experiencing GVHD are at a higher risk for infections such as herpes viruses, varicella-zoster virus (VZV), EBV-related post-transplant lymphorpoliferative disease, community respiratory viruses (CRV), (RSV) and bacteria influenza and pneumonia viruses.  (CDC, 2000)  In this paper, the focus is on the treatment, management and prevention of respiratory viruses, such as the respiratory syncytial virus (RSV), parainfluenza and adenovirus.  Community respiratory viruses, also known as CRVs, not only cause infections in the community, but are highly correlated with pneumonia and mortality in recipients of hematopoietic stem cell transplants (Nichols et al., 2001).  The most common respiratory tract infections in HSCT patients are the respiratory syncytial virus (RSV), parainfluenza and influenza (Chemaly et al, 2011; Hicks et al., 2003; Whimbey et al., 1997).  In the past, the opportunistic bacteria and fungi were the main focus in HSCT recipients; however, current research has geared towards respiratory viruses as the main infection in recipients of HSCT. (Chemaly et al., 2011)

Respiratory Syncytial Virus

Respiratory Syncytial Virus (RSV) is from the Paramyxoviridae family, genus Pneumovirus.  Most RSV infections are found in infants and young children worldwide, usually during the winter months (Chemaly et al., 2011; Kasper et al., 2001; Peret et al., 1998).  The virus itself is an RNA virus measuring about 150-300 nm in diameter and containing a nucleocapsid lipid envelope.  The envelope is comprised of two glycoproteins, a G protein and F protein, which attaches to the cell surface and allows the internal factors to pass into the cell after adhesion, respectively. These two glycoproteins are a vital part to the pathogenesis of RSV into the host cell (Chemaly et al., 2011; Hall, 2006; Hicks et al., 2003; Kasper et al., 2001).

RSV transmission is highly contagious and is spread by infectious secretions of large droplets or fomites that enter via the eyes or nose and can last on surfaces for several hours as well as human skin for over a half an hour (Laning, 2007).  The incubation period is usually 4-6 days with viral shedding occurring 1-2 before and 1-2 weeks after symptoms. (Chemaly et al., 2011; Children’s National Medical Center)  The primary infection in infants and children start as rhinorrhea in the upper respiratory tract for about 2-3 days with a low-grade fever and cough.  It progresses to the lower respiratory tract leading to a lower respiratory infection (LRI), further leading to bronchiolitis or pneumonia. (Chemaly et al., 2011; Kasper et al., 2001; Glezen et al., 1986)  In adults, there are also upper respiratory tract symptoms, with possible fever as well. In particular immunocompromised individuals and individuals with cancer or HSCT recipients have shown to progress to lower respiratory tract infections with wheezing and shortness of breath (Kasper et al., 2001; Hall et al., 2001; Walsh et al., 1999; Wald et al., 1995).  There has been significant increase in morbidity and mortality of RSV in immunocompromised patients, such as HSCT patients (Chemaly et al., 2011; Laning, 2007).  “From 1989 to 1999, RSV infection developed in 171 of 3897 HSCT recipients (Nichols et al., 2001)”.

Diagnosis

All HSCT recipients with respiratory virus symptoms undergo nasopharyngeal wash and throat swab specimen analysis.  The specimens are tested for community respiratory viruses (CRVs) using direct florescent antibody tests and shell vial culture analysis. (Nichols et al., 2001)  It is also recommended that the recipient undergoes two diagnostic samples taken two days apart to rule out a respiratory pathogen.  In addition, it is suggested that the patient has a bronchoalveolar lavage or BAL performed.  It is critical to diagnose RSV early as their illness can become fatal (Hertz et al., 1989; Martin et al., 1988).   It has been reported that RSV infections can start as an Upper Respiratory Infection (URI) and then progress to a Lower Respiratory Infection (LRI) in 30-60% of HSCT recipients.  This therefore leads to further complications, such as respiratory failure and death.   (Whimbey et al., 2005; Hertz et al., 1989)

Treatment

Since there is no vaccine for RSV available, treatment for recipients of HSCT with confirmed RSV begins with the practice of decreasing the symptoms and trying to prevent the progression of the virus to a lower respiratory infection.  In addition, it is recommended for patients to use humidifiers and humidified oxygen to improve oxygenation to the lungs (Laning, 2007)  Patients with symptoms in the upper respiratory tract are given non-steroidal anti-inflammatory drugs and antihistamines. (Chelamy et al., 2011)   For patients exhibiting a lower respiratory tract infection, strategies such as the usage of aerosolized ribavirin (Nichols et al., 2001; CDC, 2000; Win et al., 1992; Hertz et al., 1989), RSV antibodies in combination with aerosolized ribavirin (CDC, 2000; DeVincenzo et al., 1996; Whimbey et al., 1995), and RSV monoclonal antibody (CDC, 2000; Boeckh et al., 1998).   Currently, there are two different methods used in the treatment using the aerosolized ribavirin, referred to as continuous and intermittent.  Aerosolized ribavirin has been reported to be beneficial in some adults and children with LRIs. In addition, using aerosolized ribavirin early on in HSCT recipients has shown a decrease in morbidity and mortality. (Kasper et al., 2001; McColl et al., 1998)   The continuous treatment is a 6 g dosage administered daily over an 18 hour period via particle aerosol generator. The intermittent method, 60mg/ml is administered over three hours every eight hours. (Chelamy et al., 2011).  The exact treatment and best method for HSCT patients diagnosed with RSV is currently undergoing clinical trials (CDC, 2000).

Prevention

In order to prevent RSV from occurring in HSCT patients, it is recommended for patients to practice general safety precautions such as frequent hand washing and sanitizing, isolation from people with illnesses, avoidance of second hand smoke, day care and crowds, hospitalized individuals during the RSV season (Laning, 2007).   In addition, it is suggested that patients receiving the RSV antibody therapy during the RSV season (American Academy of Pediatrics, 2000).

Influenza

Influenza viruses infect the upper and lower respiratory tracts causing acute respiratory illnesses.  There are three different types of influenza viruses, A, B and C, from the Orthomyxoviridae family, with type A being the most common.  In addition, there are three hemagglutinin subtypes (H1, H2, and H3) and two neuraminidase subtypes (N1 and N2) that have been found in the influenza A viruses.  Influenza viruses are RNA viruses and the type depends on the antigenic type of nucleoprotein and matrix protein antigens. (Chemaly et al., 2011).  Influenza has a brief incubation time and a quick onset of symptoms, such as fever, chills, headache, myalgia and malaise, as well as a runny nose, sore throat and cough.  It is also common for influenza to progress to pneumonia in normal individuals, but especially in individuals who are immunocompromised, such as HSCT recipients (Chemaly et al., 2011; ACIP, 2009).  Influenza infections can increase morbidity and mortality rates in cancer patients and it has been indicated that influenza infections in HSCT patients to be reported at 0.4% (Chemaly et al., 2011; Nichols et al., 2004) and with a mortality rate of 38% (Chemaly et al., 2007).  The normal immune response for influenza is the release of type I INFs and influx of granulocytes and natural killer cells to recognize and kill influenza virus infected cells (Ljungman and Avetisyan, 2008; Mandelboim et al., 2001).  Recipients of HSCT are immunocomprimised, and therefore, do not have the normal immune response, therefore, the primary method for influenza prevention in HSCT recipients is through vaccination. (Ljungman and Avetisyan, 2008)

Diagnosis

The influenza virus is usually diagnosed in individuals exhibiting the symptoms of the virus during an influenza epidemic; however, other viruses produce the same types of symptoms and therefore, it is sometimes necessary to perform a culture analysis to detect the virus or viral antigens in nasal and throat swabs, respiratory secretions and bronchoalveolar specimens.  These types of cultures usually take up to 4 days to obtain results. (Chemaly, 2011)  In addition to cultures, there are immunoflourescence assays, enzyme immunoassays, and polymerase chain reaction (PCR)-based testing used for influenza diagnosis with only a few hour turnaround (Rodriquez et al., 2002)

Treatment

The impact of seasonal influenza has been reported in HSCT recipients with complications leading to lower airway disease and the need for mechanical ventilation, as well as mortality.  (Redelman-Sidi et al., 2010)  Treatment, therefore, is necessary immediately for patients with symptoms, preferably within 48 hours after initial symptoms (Updated Interim Recommendations).  There are two different drug classes offered in order to treat seasonal influenza infections, neuraminidase and M2 inhibitors.  The neuraminidase inhibitors are zanamivir and oseltamivir, which fight against influenza type A and B.  (Fiore et al., 2008).   The M2 inhibitors, amantadine and rimantadine, fight against influenza A.  (Ong et al., 2006)  There is however, another type of influenza A H1N1 virus.  This virus was initially swine origin and infected a human in 2009.  The 2009 H1NI Influenza outbreak in individuals with cancer is still currently begin researched; however, there have been several studies reporting different cases of severe disease in cancer patients, to include HSCT recipients.  Due to the lack of sufficient data and research, however, it cannot be concluded that the patients who contracted the H1NI in 2009 are representative of the entire population of both cancer and HSCT recipients. (Redelman-Sidi et al., 2010)

Prevention

Prevention of influenza virus in HSCT recipients is key to a healthy recovery.  Vaccination is available for both recipients and family members or close contacts.  There are two different types of vaccines available. The intranasal vaccine can only be used in healthy individuals ages 2 to 49, not individuals who are immunocompromised or allergic to eggs (Kamboj and Sepkowitz, 2007),  The other form, the intramuscular vaccine is a chemoprophylaxis and can be used in patients at high risk for complications or patients within the first 6 months of HSCT (Chemaly et al., 2011).  It is recommended for individuals to receive the vaccination before each season and after each season for at least 2 years after >6 months after HSCT (CDC, 2000b; Hayden et al., 1997; Engelhard et al., 1993) For HSCT recipients who received the stem cell therapy less than six months should receive chemoprophylaxis with amantadine or rimantadine during community influenza A outbreaks, although those drugs are not effective against influenza B.  ). Additionally, to allow sufficient time for the patient to experience an immunologic response to influenza vaccine, chemoprophylaxis with amantadine or rimantadine can be used for these HSCT recipients for 2 weeks after vaccination during nosocomial or community influenza A outbreak (CDC, 2000a).  “Influenza A chemoprophylaxis with amantadine or rimantadine has been recommended for all influenza A-exposed HSCT recipients <24 months after HSCT or >24 months after HSCT and substantially immunocompromised regardless of vaccination history, because of their likely suboptimal immunologic response to influenza vaccine (CDC, 2000a; Hayden et al., 1997; Engelhard et al. 1993)”.  It has also been recommended to start early preemptive therapy with amantadine or rimantadine with undiagnosed acute URI or LRI symptoms, especially during a community outbreak of influenza A (CDC, 2000a; CDC, 2000b).  In addition, the neuroaminidase inhibitors, intravenous and aerosol ribavirin and drug therapy using rimantadine or amantadine with ribavirin or interferon have been suggested for clinical trials to prevent influenza in HSCT recipients (Hayden et al., 1997; Hayden et al., 1996a; Hayden et al., 1996b; Hayden et al., 1996c; Knight et al., 1987)   For pediatric HSCT recipients over that age of six months, the annual seasonal influenza vaccination is recommended.  For children less than age nine and who are receiving the vaccination for the first time are required to receive two dosages one month apart. (CDC, 2000b).  Amantadine and rimantadine are not FDA-approved for children less than one year of age (American Academy of Pediatrics, 2000; CDC, 2000a; CDC, 200b).

Parainfluenza

The parainfluenza viruses (PIV) are also RNA viruses belonging to the Paramyxoviridae family. The envelope surrounding the PIV contains a hemagglutinin and neuraminidase protein.   There are five different types that share specific antigens, PIV-3 is the most common and is found during the spring and summer.  PIV-3 is associated with pneumonia and bronchiolitis in infants. The PIV-1 and 2 forms are associated with croup in children and mostly occurring during the fall season. (Chelamy et al., 2011; Henrickson et al., 1995; Walker et al., 1994)  Individuals with PIV infections can exhibit mild upper respiratory tract infections to severe infections, such as pneumonia.  The incubation period for PIV is between two to six days. Individuals with immunocompromised systems are at risk to develop the severe illness with possible fatal consequences (Chelamy et al., 2011; Kasper et al., 2001; Henrickson et al., 1995; Walker et al., 1994).  In addition, it has been reported that patients who have had HSCT performed are at a high risk for developing PIV-associated pneumonia (Nichols et al., 2001; Taylor et al., 1998; Zambon et al., 1998; Wendt et al., 1992); Wendt et al. (1992) reported a mortality rate up to 30%).

Diagnosis

The symptoms of PIV are very similar to other respiratory infections, therefore, laboratory analysis of nasopharyngeal washes, swabs or aspirates, throat swabs, and bronchoalveolar lavage (BAL) fluid should be performed in order to find the etiology of the illness and rule out PIV (CDC, 2000a). There are currently no vaccines for PIV, therefore, upon diagnosis of PIV, it is recommended for the HSCT recipient to receive immune-prophylaxis, chemoprophylaxis and preemptive treatment (CDC, 2000a; Englund et al., 1997; Flomenberg et al., 1994).

Treatment

There is no specific management and treatment for recipients of HSCT testing positive for PIV.  Ribavirin has been used in animal models (Gilbert et al., 1986) and Nichols et al., (2001) researched treatment with aerosolized ribavirin for LRI in HSCT recipients and found that the antiviral therapy appeared inadequate in reducing viral shedding or mortality once pneumonia persisted.  There has been some success with the use of methylprednisolone and intravenous ribavirin in the treatment of pneumonia associated with PIV (Chelamy et al., 2011; Shima et al., 2008; Wright et al., 2005).

Adenovirus

The Adenovirus, more commonly referred to as “AdV”, is from the family Adenoviridae. This particular virus is a DNA virus with 51 different subtypes.  The most common causes are subtypes 1, 2, 5, 7 and 14.  In immunocompromised patients, particularly HSCT recipients, AdV can be fatal (Lindemans et al., 2010).   “Infections due to adenovirus in HSCT recipients have a reported incidence of 0.5% – 3% and are more commonly reported in allogeneic HSCT recipients than in autologous transplant recipients (6% v. 0.92%) (Chelamy et al., 2011)”. AdV causes mild respiratory symptoms and gastrointestinal disease in healthy individuals; however, immunocompromised patients can develop severe respiratory disease, hepatitis, and colitis.  In adults, infections are characterized by sore throat, fever and cough. In addition, the most common clinical symptoms besides respiratory symptoms are fever and diarrhea (Kasper et al., 2001).  Other complications such as hemorrhagic cystitis and adenoviral keratoconjunctivitis can occur as well. (Lindemans et al., 2010).  Furthermore, co-infections with Aspergillus spp, and bacteria such as Nocardia, Legionella spp, and Mycobacterium tuberculosis are frequently seen (Chelamy et al., 2011).

Diagnosis

The diagnosis of Adenovirus infection is usually suspected when the patient exhibits acute respiratory disease, especially in known community outbreaks. This respiratory virus, like other respiration infections, cannot be diagnosed from the clinical symptoms (Kasper et al., 2001).  A diagnosis must be made using laboratory methods such as viral cultures, ELISA or PCR based assays. In addition, viral load quantification is used to measure and monitor the individual response (Lankester et al., 2004; Leruez-Ville et al., 2004).  Furthermore, viral load quantification is used as a tool to make sure individual loads are not higher than 1×10⁶copies/mL as this measurement has been associated with higher mortality. (Claas et al., 2005; Schilham et al., 2003)

Treatment

Current available antiviral treatments for AdV are known to be toxic; therefore, it is imperative to detect AdV disease immediately in patients that are at risk, such as HSCT recipients.  The monitoring of AdV in the peripheral blood using quantitative AdV polymerase chain reaction (PCR) is a more effective method than viral cultures or fluorescent assays (Damen et al., 2008; Kuypers et al., 2006).  In addition, weekly monitoring in HSCT patients seems to be necessary because of the rapid AdV replication (Lindemans et al., 2010).

There are many different treatment options for HSCT recipients with a positive AdV result.  For instance, antiviral drugs, such as ribavirin and cidofovir, are used to treat AdV. Cidofovir inhibits viral DNA replication due to its monophosphate nucleotide analog of cytosine that is phosphorylated intracellularly to a diphosphate (Lindemans et al., 2010).   Cidofovir has proven to be an effective agent against AdV; however, its effects are toxic.  Cidofovir is excreted in the urine through the proximal tubule cells and the cidofovir seems to accumulate in the tubule lumen leading to tubular necrosis (Lindemans et al., 2010).  Although nephrotoxicity is common in patients using cidofovir, there are two treatments regimens that are used. The patients receive 5 mg/kg every 1–2 weeks or 1 mg/kg three times per week (Doan et al., 2007).

Prevention

The combination of the antiviral therapy with ribavirin prophylaxis has proven to result in significantly lower incidence of AdV infection and mortality (Lindemans et al., 2010; Griel et al.,2006).  In addition, immunotherapy is a suggested method for management in HSCT patients with AdV.  Due to the limitations and toxicity of other AdV treatments, it is suggested that cellular immunotherapeutic approaches are used to transfer T-cells with AdV specificity into the HSCT recipient.  This helps fight the AdV infection and prevent serious illness. (Lindemans et al., 2010).

Currently, there are novel drugs being developed to alleviate the problems with the antiviral drugs that are available.  These include ganciclovir triphosphate and S-2242 compound.  These drugs are being developed to increase in oral bioavailability and decrease the nephrotoxicity, as seen in the cidofovir. (Lindemans et al., 2010)

Rhinovirus

The Rhinovirus from the family Picornaviridae, is another RNA virus that causing respiratory illnesses.  There are over 100 serotypes of the Rhinovirus, which leads to the lack of vaccines (Kasper et al., 2001).  Rhinoviruses are the cause of the common cold, where adults obtain around 2-3 colds per year and children around 8-12 (Kasper et al., 2001; Winther et al., 1998).  This virus is also seasonal and is highly contagious through self-inoculation or contact with respiratory droplets (Kasper et al., 2001).  The symptoms of rhinovirus are the common cold symptoms with a runny nose, cough or sore throat.  The symptoms usually last 2-9 days and are usually not associated with lower respiratory diseases.  Although, the rhinoviruses usually don’t lead to LRI in healthy individuals, individuals who are immunocompromised are at higher risk for infections. One study in HSCT recipients found that 32% of patients who had rhinovirus infections died of pneumonia (Ghosh et al., 1999) There are no specific treatments for rhinoviruses; however, management of rhinovirus in HSCT follows the same regime for healthy individuals through the use of antihistamines, anti-inflammatory drugs and decongestants.  In addition, prevention is simply sanitizing, washing hands and staying away from individuals with cold symptoms.  (Chelamy et al., 2011)

Other Viruses

There are a couple other viruses that cause respiratory illnesses that are monitored in HSCT patients. The coronavirus and human metapneumovirus (hMPV) . These viruses have the same types of symptoms as the rhinovirus such as coughs, nasal congestion and wheezing.  There have been some recent reported cases of immunocompromised patients with coronaviruses; however, there has been no studies conducted in cancer patients with these diseases.  In addition, one reported case of a HSCT recipient with a diagnosis of coronavirus was treated successfully using basic cold techniques (Folz et al., 1999). In another study, the hMPV infection was studied. It was reported that 9% of patients with hematologic malignancies had hMPV infection, with nine of the patients HSCT recipients.  (Williams et al., 2005)  In addition, in another study, five out of 163 HSCT recipients tested positive for the presence of hMPV in the broncho-alveolar lavage specimen analysis (Chemaly et al., 2011).

There is currently no specific antiviral therapy for either coronavirus and human metapneumovirus (hMPV); therefore, the management and treatment for recipients testing positive for these viruses follows the same regime as the rhinovirus, use of antihistamine and anti-inflammatory drugs  (Chelamy et al., 2011)

Conclusion

After HSCT has been performed on a patient, there are predictable immune system deficiencies and recoveries which the recipient undergoes, especially in regard to respiratory illnesses.  The patient is treated with chemotherapy or radiation therapy before receiving the HSCT and therefore opens a series of opportunities for viruses and bacteria to invade the recipient and cause serious disease.

There are many serious respiratory illnesses that can cause severe illness in HSCT patients.  Preventing respiratory illnesses in HSCT patients, therefore, is critical. In order to prevent transmission of respiratory diseases, it is recommended for HSCT recipients and their family and close friends to follow specific infection control guidelines, as well as medical staff to follow the recommended Phases per the CDC (2000a).  These guidelines reduce the risk for respiratory illness which can lead to fatal conditions, such as pneumonia. In addition, active monitoring for all upper and lower respiratory diseases should be conducted for all hospitalized HSCT recipients, as well as the patients undergoing HSCT.  (CDC, 2000a)  The monitoring should consist of daily screening for all signs and symptoms, such as runny nose, sneezing, coughing, sore throat, etc.  In addition, any HSCT recipients with respiratory tract illness symptoms should be placed under strict precautions to avoid transmitting infections to other patients. (CDC, 2000a)

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