Ribavirin for Inhalation Use

Number: 0155

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses ribavirin for inhalation use.

1. Criteria for Initial Approval

   Aetna considers ribavirin inhalation medically necessary for the treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus (RSV).

   Aetna considers all other indications as experimental, investigational, or unproven.
   

2. Related Policies

   1. CPB 0318 - Palivizumab (Synagis)
   2. CPB 1027 - Respiratory Syncytial Virus (RSV) Vaccines for Adult and Maternal Use
   3. CPB 1038 - Nirsevimab-alip (Beyfortus)
   4. CPB 1088 - Clesrovimab-cfor (Enflonsia)

Dosage and Administration

Ribavirin for Inhalation Solution, USP is supplied in a one-pack count containing 100 mL glass vial with 6 grams of sterile, lyophilized drug which is to be reconstituted with 300 mL Sterile Water for Injection, USP or Sterile Water for Inhalation (no preservatives added) and administered only by a small particle aerosol generator (SPAG-2).

Ribavirin for Inhalation Solution, USP is indicated for the treatment of hospitalized infants and young children with severe lower respiratory tract infections due to RSV. Treatment early in the course of severe lower respiratory tract infection may be necessary to achieve efficacy. Ribavirin for inhalation is not indicated for use in adults.

The recommended treatment regimen is 20 mg/mL Ribavirin for Inhalation Solution, USP as the starting solution in the drug reservoir of the SPAG-2 unit, with continuous aerosol administration for 12-18 hours per day for 3 to 7 days. Using the recommended drug concentration of 20 mg/mL the average aerosol concentration for a 12 hour delivery period would be 190 mcg/L of air. Aerosolized Ribavirin for Inhalation Solution, USP should not be administered in a mixture for combined aerosolization or simultaneously with other aerosolized medications.

Source: Hospira, 2019

Experimental, Investigational, or Unproven

Ribavirin inhalation is considered experimental, investigational, or unproven for all other indications because the effectiveness of these approaches has not been established (not an all-inclusive list):

• Acute myeloid leukemia;
• Coronavirus disease 2019 (COVID-19);
• Foot-and-mouth disease;
• Glioblastomas;
• Hepatitis E infection;
• Multiple sclerosis, oral cancer;
• Oral cancer;
• Parainfluenza viral infections in immunocompromised individuals;
• Thyroid cancer.

Cationic liposome encapsulated ribavirin spray is considered experimental, investigational, or unproven for the treatment of acute pneumonia.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
90378	Respiratory syncytial virus, monoclonal antibody, recombinant for intramuscular use, 50 mg each
HCPCS codes covered if selection criteria are met:
Ribavirin Inhalation - no specific code
HCPCS codes not covered for indications listed in the CPB:
Cationic liposome encapsulated ribavirin spray – No specific code
ICD-10 codes covered if selection criteria are met:
B97.4	Respiratory syncytial virus (RSV) as the cause of diseases classified elsewhere
J12.1	Respiratory syncytial virus pneumonia
J20.5	Acute bronchitis due to respiratory syncytial virus
J21.0	Acute bronchiolitis due to respiratory syncytial virus (RSV)
ICD-10 codes not covered for indications listed in the CPB:
B08.4	Enteroviral vesicular stomatitis with exanthem
B17.2	Acute hepatitis E
C00.0 - C10.9	Malignant neoplasm of lip and oral cavity
C72.0 - C72.9	Malignant neoplasm of central nervous system [glioblastoma]
C73	Malignant neoplasm of thyroid gland
C92.00 - C92.92	Myeloid leukemia
D00.00 - D00.08	Carcinoma in situ of lip, oral cavity, and pharynx
D37.01 - D37.02, D37.04 - D37.09	Neoplasm of uncertain behavior of lip, oral cavity, and pharynx
G35.A - G35.D	Multiple sclerosis
J12.2	Parainfluenza virus pneumonia
J12.82	Pneumonia due to coronavirus disease 2019
J18.9	Pneumonia, unspecified organism
J20.4	Acute bronchitis due to parainfluenza virus
U07.1	COVID-19

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Ribavirin for inhalation solution, USP is indicated for the treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus (RSV).

Ribavirin for inhalation use is a synthetic guanosine analog antiviral that exhibits selective inhibitory activity against respiratory syncytial virus (RSV) in cell cultures, although its exact mechanism of action remains unknown. The reversal of its in vitro antiviral activity by guanosine or xanthosine suggests that ribavirin may function as an analogue of these cellular metabolites. It has demonstrated antiviral activity against RSV both in vitro and in experimentally infected cotton rats. In studies evaluating several clinical isolates of RSV for ribavirin susceptibility through plaque reduction in tissue culture, plaques were reduced by 85-98% at a concentration of 16 mcg/mL, though results may vary depending on the test system used. The development of resistance to ribavirin has not been assessed in vitro or in clinical trials. Additionally, ribavirin has shown in vitro activity against influenza A and B viruses and herpes simplex virus, but the clinical significance of these findings is unclear. When administered by aerosol, Ribavirin for Inhalation Solution, USP, is absorbed systemically.

Ribavirin for Inhalation Solution, USP is contraindicated in individuals with a known hypersensitivity to the drug or its components, as well as in women who are pregnant or may become pregnant during treatment. The drug has shown significant teratogenic and/or embryocidal effects in all animal species studied, including rodents and rabbits. Consequently, while clinical studies in humans have not been conducted, it is prudent to assume that Ribavirin for Inhalation Solution, USP may pose a risk of fetal harm. Additionally, systemic studies indicate that ribavirin is concentrated in red blood cells and remains in the body for the lifespan of the erythrocyte.

Ribavirin for inhalation solution includes boxed warnings indicating that its use in patients requiring mechanical ventilator assistance should only be conducted by physicians and support staff who are familiar with the specific ventilator and this method of drug administration. It is crucial to adhere to procedures that minimize the accumulation of drug precipitate, as this can lead to mechanical ventilator dysfunction and increased pulmonary pressures. There have been reports of sudden respiratory function deterioration associated with the initiation of aerosolized ribavirin treatment in infants, necessitating careful monitoring of respiratory status during therapy. If a sudden decline in respiratory function occurs, treatment should be halted and can only be resumed with extreme caution, continuous monitoring, and consideration of concurrent bronchodilator administration. Ribavirin for inhalation solution is not indicated for adult use. Additionally, both physicians and patients should be aware that ribavirin has been shown to cause testicular lesions in rodents and is teratogenic in all animal species studied, including rodents and rabbits.

Patients suffering from severe lower respiratory tract infections caused by RSV require careful monitoring of their respiratory and fluid status, as outlined in the SPAG-2 Instructions for Use. There have been no clinical studies investigating the interactions of Ribavirin for Inhalation Solution, USP with other medications commonly used to treat infants with RSV, such as digoxin, bronchodilators, antiviral agents, antibiotics, or anti-metabolites. Additionally, the potential interference of Ribavirin with laboratory tests has not been assessed.

Ribavirin has been shown to increase the incidence of cell transformations and mutations in specific mouse cell lines at certain concentrations. In vivo studies indicate that ribavirin may induce benign tumors in rats, although the carcinogenic potential remains inconclusive. Furthermore, ribavirin has demonstrated significant teratogenic and embryocidal effects in various animal species, with malformations observed at doses that are considered to pose a risk to fetal development. While the effects on fertility in ribavirin-treated animals have not been fully explored, significant testicular damage has been noted in male mice and rats. Given that ribavirin is concentrated in red blood cells and persists for their lifespan, the potential for fetal harm in humans cannot be ruled out, and the minimum safe interval before pregnancy following exposure is unknown.

Ribavirin for Inhalation Solution, USP has been found to be toxic to lactating animals and their offspring, though it is unclear if it is excreted in human milk. Health care workers caring for patients receiving aerosolized ribavirin should be aware of its teratogenic potential, as studies have shown that the drug can disperse into the immediate environment during patient care. Although no confirmed cases of teratogenesis have been reported in offspring of mothers exposed to aerosolized ribavirin, the lack of controlled studies in pregnant women necessitates caution. A study by the National Institute of Occupational Safety and Health (NIOSH) indicated measurable urine levels of ribavirin in health care workers, with the highest levels found in those administering the drug via oxygen tents. Hospitals are encouraged to implement training programs to minimize occupational exposure, and pregnant health care workers should consider avoiding direct patient care involving aerosolized ribavirin.

Adverse reactions associated with aerosolized Ribavirin for Inhalation Solution, USP have been documented in clinical studies and post-marketing reports. There have been instances of death during or shortly after treatment, particularly in infants with worsening respiratory conditions or mechanical ventilator malfunctions. Pulmonary function deterioration has been observed in adults with chronic lung diseases, and serious adverse events have been reported in infants with severe underlying conditions. Common pulmonary complications include bronchospasm, pulmonary edema, and apnea, while cardiovascular issues such as cardiac arrest and hypotension have also been noted. Although anemia was not reported in controlled trials, it has been associated with ribavirin use in other contexts. Other adverse effects include rash, conjunctivitis, and in rare cases, seizures. Health care workers have reported various symptoms, including headaches and conjunctivitis, following exposure to aerosolized ribavirin, although most symptoms resolved quickly after discontinuation of exposure. Given the potential for RSV to spread, hospitals should maintain strict infection control measures to protect uninfected patients.

Respiratory Syncytial Virus (RSV)

Respiratory syncytial virus (RSV) is an enveloped, single-stranded, negative-sense ribonucleic acid (RNA) virus belonging to the Pneumoviridae family, capable of causing acute respiratory tract illness in individuals of all ages. RSV is considered a common respiratory pathogen, typically resulting in self-limited, mild, cold-like symptoms that can last around one to two weeks. However, for some individuals, the virus can lead to an infection that spreads to the lower respiratory tract, causing bronchiolitis or pneumonia, which can result in severe or life-threatening illness. Those most vulnerable to severe infection include infants (especially premature infants), older adults (particularly those aged 65 years and older), individuals with certain comorbid conditions (e.g., cardiac and pulmonary diseases), and those who are immunocompromised. In most parts of the United States, RSV circulation is seasonal, typically starting in the fall and peaking in the winter. The virus is transmitted from person to person through close contact with infected individuals.

Ribavirin inhalation, branded as Virazole (Bausch Health), was FDA‑approved in 1986 for the treatment of serious RSV infection in hospitalized infants, supported primarily by early double‑blind, placebo‑controlled clinical trials demonstrating reduced illness severity and antiviral activity against RSV, alongside robust preclinical data showing selective RSV inhibition in vitro and efficacy in cotton rat models; these findings were later synthesized in the 1993 American Academy of Pediatrics review, which reaffirmed its antiviral effectiveness while noting practical limitations related to delivery method, toxicity concerns, and variability in clinical response. 

Avery and colleagues (2020) stated that RSV-associated lower respiratory tract infection (LRTI) is a concern in immunocompromised patients. Aerosolized ribavirin (RBV AER) is used for the treatment of RSV LRTI; however, adverse events (AEs) and rising drug costs remain challenges for patient management. In a systematic review, these investigators examined the efficacy and AE profile of RBV AER for the treatment of hospitalized RSV LRTI in immunocompromised adult patients. They conducted a search across Medline/PubMed, Embase, Google Scholar, ClinicalTrials.gov, and the Cochrane Library from 1966 to January 2019 for the use of RBV AER. The search strategy included [(ribavirin OR ICN1229) AND ("administration, oral" OR "oral" OR "administration, inhalation" OR "inhalation")] AND ("respiratory tract infection" OR "pneumonia"). Studies were reviewed if adult patients were hospitalized, immunocompromised, had RSV LRTI, received RBV AER, and included outcomes of mortality and/or adverse reactions. Methodological quality was evaluated using the Cochrane Collaboration GRADE approach. A total of 1,787 records were identified, and 15 articles met the inclusion criteria: hematopoietic stem cell transplant (HSCT)/bone marrow transplant (n = 8), other malignancy/neutropenic (n = 2), and solid organ transplant (n = 5). All of the trials were observational with a low-quality rating; thus, a meta-analysis was not conducted. The 30-day mortality in studies that included more than 10 patients with HSCT, malignancy, and transplant ranged from 0% to 15.4%, 6.3%, and 0% to 27%, respectively. Improved mortality was cited in four studies when RBV AER was started before mechanical ventilation or within two weeks of symptom onset. Only three studies had comparative mortality data with RBV AER and oral RBV; AEs were reported in five studies and included psychiatric manifestations (anxiety, depression, feelings of isolation; n = 14), wheezing/bronchospasm (n = 6), sensations of snowflakes/hail blowing in the face (n = 6), and precipitation in ventilator tubing (n = 5). The authors concluded that there is a lack of high-quality, comparative trials on the use of RBV AER for the treatment of RSV LRTI in adult hospitalized immunocompromised patients. There may be a mortality benefit when RBV AER is initiated early after diagnosis or prior to mechanical ventilation, but this requires further study. Patient isolation and psychological effects must be weighed against the benefits of therapy.

In a systematic review and meta-analysis, Tejada et al. (2022) aimed to evaluate the efficacy and safety of ribavirin in patients diagnosed with respiratory syncytial virus (RSV) associated with lower respiratory tract infections (LRTI). The review included observational studies and randomized controlled trials involving subjects treated with aerosolized or oral ribavirin, with supportive care or placebo as comparators. A comprehensive search of PubMed, Cochrane Library, and Web of Science databases was conducted from January 2001 to January 2022, registered under PROSPERO number CRD42022308147. Out of 907 studies retrieved, 10 observational studies and 1 randomized controlled trial were included, with 4 out of 11 demonstrating high quality of evidence. The analysis encompassed 788 subjects with RSV infection, of which 14.3% had only LRTI. Among the 445 subjects treated with ribavirin, 195 (43.8%) received the aerosolized formulation. The pooled meta-analysis revealed no significant difference in mortality (risk ratio [RR]: 0.63; 95% confidence interval [CI]: 0.28-1.42) between those treated with ribavirin and supportive care. However, subgroup analysis indicated significantly lower mortality in patients with hematological malignancies (RR: 0.32; 95% CI: 0.14-0.71), while no significant difference was observed in lung transplant recipients (RR: 0.89; 95% CI: 0.31-2.56). Additionally, oral ribavirin was associated with increased viral clearance (RR: 2.60; 95% CI: 1.35-4.99). Seventeen adverse events were reported among 119 subjects, but none were severe. The authors concluded that ribavirin should be considered for treating RSV-LRTI in hematological patients, although evidence for its use in lung transplant recipients is lacking. Furthermore, the oral formulation is suggested as a safer, easier, and more cost-effective alternative to aerosolized ribavirin, with a call for further research into newer antiviral options.

Bausch Health discontinued Virazole in mid-2025. Cameron Pharmaceuticals discontinued generic formulations of ribavirin inhalation in 2025. Zydus discontinued ribavirin inhalation in late-2025 (ASHP, 2026).

Cationic Liposome Encapsulated Ribavirin Spray for the Treatment of Acute Pneumonia

Wang et al. (2024) noted that acute pneumonia (AP), triggered primarily by pathogens like bacteria and viruses, is a leading cause of human mortality. Ribavirin plays an important role in the treatment of AP; however, its therapeutic use is hindered by the need for high dosages and the associated cardiac and hepatic toxicities. These researchers synthesized polyethylene glycol-modified cationic liposomes to encapsulate ribavirin (RBV-PCL) and formulated it into a spray, aiming to enhance the effectiveness of RBV via respiratory administration. Lipopolysaccharide (LPS), a compound known to induce AP models in animals, was employed in this study. These investigators successfully established an AP model in mice using aerosol inhalation. Through animal experiments, they examined the therapeutic effects of RBV-PCL on mice with AP.  In-vivo studies demonstrated promising results. RBV-PCL effectively prolonged the survival of mice with AP, significantly reduced the levels of inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and inhibited the infiltration of neutrophils in the lungs and spleens of mice. The authors concluded that PCL liposomes are expected to be effective drug delivery vehicles, and RBV-PCL is also expected to be a potential drug for the treatment of AP.

Coronavirus Disease 2019 (COVID-19)

Perveen and colleagues (2020) stated that there are several attempts to find an effective antiviral drug against the coronavirus disease 2019 (COVID-19). Although the majority of COVID-19 patients have mild-to-moderate clinical events, up to 5% to 10% may have severe, life-threatening events that urgently require effective medications. In a systematic review, these investigators examined the effectiveness of antiviral therapies in the treatment of COVID-19. They carried out an extensive search in PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs), prospective case-series studies that examined therapies for patients with COVID-19. The outcomes searched for were mortality, recovery rate, hospital length of stay (LOS), as well as clinical improvement from January to May 15, 2020. Independent reviewers searched, identified, screened, and included relevant studies. A total of 5 RCTs on 439 patients and 17 case-series studies involving 1,656 patients were found in the specified review period that reported the use of lopinavir, ritonavir, remdesivir, oseltamivir, and ribavirin in patients with COVID-19; but none of which showed effectiveness of antiviral therapy. Such current findings impeded researchers from recommending an appropriate and effective antiviral therapy against COVID-19, making it a serious concern for the global community. The authors concluded that in the present pandemic and any future epidemics, all the related authorities should pursue many more RCTs, cohort, and case-series studies for a prospective outcome in the management and treatment guidelines.

In an observational, single-center study, Malhani and co-workers (2021) compared the safety and effectiveness of interferon (IFN)-based therapy (lopinavir/ritonavir [LPV/r], ribavirin, and IFN-beta-1b) versus favipiravir (FPV) in a cohort of hospitalized patients with non-critical COVID-19. Allocation to either treatment group was non-random but based on changes to national treatment protocols rather than physicians' selection (quasi-experimental). These researchers examined the association between IFN-based therapy and 28-day mortality using a Cox regression model with treatment as a time-dependent covariate. The study cohort included 222 patients, of whom 68 (28%) received IFN-based therapy. Antiviral therapy was started at a median of 5 days (3 to 6 days) from symptom onset in the IFN group versus 6 days (4 to 7 days) for the FPV group, p < 0.0001. IFN-based therapy was associated with a lower 28-day mortality as compared to FPV (6 (9%) versus 18 (12%)), adjusted HR [aHR] (95% CI: 0.27 (0.08 to 0.88)). No difference in hospitalization duration between the two groups, 9 (7 to 14) days versus 9 (7 to 13) days, p = 0.732 was found. The IFN-treated group required less use of systemic corticosteroids (57%) as compared to FPV (77%), p = 0.005 after adjusting for disease severity and other confounders. Patients in the IFN-treated group were more likely to have nausea and diarrhea as compared to the FPV group (13% versus 3%), p = 0.013 and (18%) versus (3%), p < 0.0001, respectively. The authors concluded that in this quasi-experimental comparative analysis of hospitalized patients with non-critical COVID-19, they observed that early IFN-based triple therapy was associated with better outcomes as compared to FPV with a statistically significant reduction in mortality at 28 days and a reduced need for adjunctive systemic corticosteroids. Moreover, these researchers stated that future RCTs are needed to compare these two therapeutic regimens.

The authors stated that this study had several drawbacks. First, this trial was not an RCT; thus, these investigators could not completely rule out the effect of unmeasured or residual confounding or treatment selection bias. Second, the low number of events limited the ability to adjust for many potential confounders in the Cox model. Third, because the study protocol did not allow the use of IFN-based therapy 7 days after symptom onset, these researchers could not compare the effect of early versus late IFN on outcomes. Fourth, this trial was a single-center study. Fifth, although pre-hospital treatment might have affected patients’ outcomes, these researchers believed that it was unlikely to affect their findings since the majority of patients received either no pre-hospital therapy due to the unavailability of effective antiviral therapy for COVID-19 in the outpatient setting at the date of the study, or very few received hydroxychloroquine in the outpatient setting. However, multiple RCTs have failed to show any benefit of hydroxychloroquine on all outcomes. Moreover, if any pre-hospital effect was present, it should cause a random error rather than bias. Furthermore, the authors had considered treatment with IFN-based therapy and FPV as time-dependent variables and adjusted for time since symptom onset to address any raised survivor bias. Finally, patients with respiratory failure requiring mechanical ventilation, acute respiratory distress syndrome (ARDS), as well as patients with cytokine release syndrome (CRS) were excluded from this trial, which limited the generalizability of these findings to critically ill patients.

In a prospective, randomized, open-label, multi-center, phase-II clinical trial, Hung and associates (2021) examined the safety and effectiveness of combined IFN-beta-1b, LPV/r, and ribavirin for treating patients with COVID-19. This study included adult patients with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million International Units (IUs) of IFN-beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 hours (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR; and was carried out in the intention-to-treat (ITT) population. Between February 10 and March 20, 2020, a total of 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to the start of study treatment was 5 days (IQR 3 to 7). The combination group had a significantly shorter median time from the start of study treatment to a negative nasopharyngeal swab (7 days [IQR 5 to 11]) than the control group (12 days [8 to 15]; HR 4.37 [95% CI: 1.86 to 10.24], p = 0.0010). AEs included self-limited nausea and diarrhea with no difference between the two groups. One patient in the control group discontinued LPV/r because of biochemical hepatitis. No patients died during the study. The authors concluded that early triple antiviral therapy was safe and superior to LPV/r alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19. Moreover, these researchers stated that future clinical studies of a double antiviral therapy with IFN-beta-1b as a backbone are needed.

The authors stated that this study had several drawbacks. This trial was open-label, without a placebo group, and confounded by a subgroup omitting IFN-beta-1b within the combination group, depending on time from symptom onset. A subsequent phase-III clinical trial with IFN-beta-1b as a backbone treatment with a placebo control group should be considered, because subgroup comparison suggested that IFN-beta-1b appeared to be a key component of the combination treatment. The absence of critically ill patients in this study did not allow the generalization of these findings to severe cases.

Zhao et al. (2021) noted that the COVID-19 pandemic has become a global public health crisis, for which antiviral treatments are considered mainstream therapeutic approaches. With the development of this pandemic, the number of clinical studies on antiviral therapy, including remdesivir, chloroquine and hydroxychloroquine, LPV/r, ribavirin, arbidol, IFN, FPV, oseltamivir, nitazoxanide, nelfinavir, and camostat mesylate, has been increasing. However, the effectiveness of these antiviral drugs for COVID-19 remains controversial. These researchers summarized the recent progress and findings on antiviral therapies, aiming to provide clinical support for the management of COVID-19. Furthermore, they analyzed the causes of controversy in antiviral drug research and discussed the quality of current studies on antiviral treatments. The authors concluded that remdesivir is currently the most potential antiviral drug for the treatment of COVID-19; the triple combination of IFN-beta-1b, LPV/r, and ribavirin was confirmed to be more effective. Moreover, these researchers stated that high-quality randomized clinical trials are needed to determine the safety and effectiveness of antiviral drugs for the treatment of patients with COVID-19.

Couroux et al. (2022) noted that previous studies suggested that ribavirin aerosol could be a safe and effective therapeutic option in the treatment of patients with coronaviruses. However, current treatment is long (12 to 18 hours per day, 3 to 7 days), limiting its clinical use. A reduction in treatment time would reduce treatment burden. In a randomized, placebo-controlled phase-I clinical trial, these researchers examined the safety and pharmacokinetics (PK) of four single-dose regimens of ribavirin aerosol in healthy volunteers. A total of 32 participants were randomized into four cohorts of aerosolized ribavirin (active) or placebo. Cohort 1 received 50 mg/ml ribavirin/placebo (10 ml total volume); cohort 2 received 50 mg/ml ribavirin/placebo (20 ml total volume); cohort 3 received 100 mg/ml ribavirin/placebo (10 ml total volume); and cohort 4 received 100 mg/ml ribavirin/placebo (20 ml total volume). Intense safety monitoring and PK sampling took place on days 1, 2, 3, and 40. Subjects were (mean ± SD, active versus placebo) aged 57 ± 4.5 versus 60 ± 2.5 years; 83% versus 88% were female; and 75% versus 50% were Caucasian. Approximately 12.5% (3/24) and 25% (2/8) experienced at least one treatment-emergent adverse event (TEAE) (2 moderate; 5 mild) in the active and placebo groups, respectively. No clinically significant safety concerns were reported. Mean maximum observed concentration (Cmax) and area under the curve (AUC) values were higher in cohort 4, whereas cohorts 2 and 3 showed similar PK values. Ribavirin absorption reached Cmax within 2 hours across cohorts. The authors concluded that four single-dose regimens of ribavirin aerosol demonstrated systemic exposure with minimal systemic effects. These researchers stated that these findings supported continued clinical development of ribavirin aerosol as a therapeutic option in patients with coronaviruses.

The authors stated that this study had several drawbacks. First, it was conducted in healthy volunteers using a single dose of ribavirin, which limited extrapolation to clinical practice and patients with disease undergoing courses of treatment. Second, inclusion criteria were strict; therefore, the impact of concurrent medications and/or diseases observed in real-world clinical practice may affect safety and PK parameters. Third, regarding the safety assessments, hematologic changes in red blood cells (RBCs) can take place up to 40 days after dosing; thus, the impact on blood cell counts may not have been observed during the window period between day 3 and day 40 assessments due to the absence of interim safety assessments. Fourth, for the PK assessments, it was acknowledged that different bioanalytical methods for total ribavirin and ribavirin in plasma have been developed and validated independently with different internal standards and limits of quantification (LOQ). This resulted in differences observed in AUC between total ribavirin and ribavirin in plasma that reflected the differences in bioanalytical methods. The LOQ was approximately 10-fold higher for total ribavirin versus ribavirin in plasma, leading to several time points being below the level of quantitation (BLQ) for total ribavirin. This has a direct impact on the total ribavirin calculated value, resulting in lower AUC values for total ribavirin. In contrast, Cmax is not sensitive to the difference in lower LOQs (LLOQs); thus, the observed Cmax values were comparable for total ribavirin versus ribavirin for all cohorts. The analytical methods have been developed and validated in compliance with the acceptance criteria of the FDA and other regulatory guidelines. Fifth, the study was carried out in one Canadian center, limiting the applicability to other healthcare systems and countries. However, this was a phase-Ia safety and PK study examining a clinically relevant administration protocol of ribavirin aerosol; the results were promising and showed that further study is needed in the clinical setting.

Poulakou et al. (2023) stated that there is an unmet medical need for effective treatments for hospitalized patients with COVID-19. Ribavirin is a broad-spectrum antiviral with demonstrated in vitro activity against multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In an open-label, non-randomized, multi-center, phase-I clinical trial, these researchers examined the potential of ribavirin inhalation solution (ribavirin aerosol) to reduce COVID-19 disease severity in adults with confirmed SARS-CoV-2 infection and a diagnosis of respiratory distress. This trial was carried out from February 2021 through August 2021. Patients received ribavirin aerosol (100 mg/ml for 30 minutes or 50 mg/ml for 60 minutes) twice daily for up to 6 days. The primary endpoint was the change from baseline in clinical status severity, rated on a 7-point scale (1 [death]; 7 [not hospitalized; no limitations on activities]), at day 7 (or end-of-treatment/early termination) and day 30 (follow-up). A total of 51 patients were treated with ribavirin aerosol (mean age of 51.5 years; 78.4% men); the mean number of doses was 9.7 (range of 1 to 12). Improvement of 1 level or higher in clinical status severity was observed in 31.4% (16/51) and 78.4% (40/51) of patients at end-of-treatment and day 30, respectively. Of 21 patients who required a ventilator, 16 (76.2%) were able to discontinue ventilator use; 5 patients (9.8%) died between end-of-treatment and day 30; 3 patients (5.9%) discontinued study treatment due to AEs. No deaths were considered related to study treatment. The authors concluded that these data provided preliminary evidence that ribavirin aerosol may be an effective treatment for respiratory distress in adults with COVID-19. These investigators stated that further research is needed to compare ribavirin aerosol with an appropriate control treatment (e.g., standard care) in a larger population of hospitalized patients with COVID-19.

The authors stated that the main drawbacks of this study were the lack of a control group, the lack of clarity regarding the contributions of concomitant medications (e.g., corticosteroids and remdesivir), as well as the absence of data regarding systemic exposure levels to ribavirin. Furthermore, the timing of assessments may have impacted the interpretation of the efficacy results. The clinical status severity (CSS) rating was not necessarily captured at relevant milestones of patients' clinical progress. For example, a number of patients had post-treatment clinical status rated as “hospitalized” in the morning, even though they were discharged from the hospital on that study day. In those situations, the CSS rating underestimated the level of improvement at the end of treatment. Additionally, because there were no scheduled assessments between days 7 and 30, the precise timing of improvement was unknown in many patients, with improvement first documented on day 30.

Parainfluenza Viral Infections in Immunocompromised Patients

Falsey and co-workers (2012) stated that parainfluenza viruses (PIV) are common respiratory viruses that belong to the Paramyxoviridae family, and PIV infection can lead to a wide variety of clinical syndromes ranging from mild upper respiratory illness to severe pneumonia. Severe disease can be seen in elderly or chronically ill persons and may be fatal in individuals with compromised immune systems, particularly children with severe combined immunodeficiency syndrome (SCIDS) and hematopoietic stem cell transplant (HSCT) recipients. Currently, there are no licensed antiviral agents for the treatment of PIV infection. Aerosolized or systemic ribavirin (RBV) in combination with intravenous gamma globulin (IVIG) has been reported in small, uncontrolled series and case reports of immunocompromised patients. Most of the information regarding the clinical utility of RBV comes from case reports or small, uncontrolled series. In children with SCIDS and PIV infection, aerosolized RBV has been administered over long periods (3 to 10 months) without apparent toxicity. The authors noted that although RBV has been well-tolerated, the efficacy for the treatment of PIV infection is difficult to determine, as most case series involve small numbers, different routes of administration, combination treatment with IVIG, and different patient populations. The majority of data were in HSCT patients, and consensus indicated that RBV is not effective for PIV pneumonia when given late in the course of illness, especially if respiratory failure has ensued. Some reports suggested a modest benefit if the drug is given at the early stage of upper respiratory tract infection (URTI), but this is controversial due to the lack of controlled trials. Most studies of HSCT patients reported RBV treatment of both URTI and lower respiratory tract infection (LRTI) of PIV and demonstrated no clear benefit of RBV treatment.

Von Lilienfeld-Toal and colleagues (2016) stated that community-acquired viruses (CRVs) may cause severe disease in cancer patients. Thus, efforts should be made to diagnose CRV rapidly and manage CRV infections accordingly. A panel of 18 clinicians from the Infectious Diseases Working Party of the German Society for Hematology and Medical Oncology convened to evaluate the available literature and provide recommendations on the management of CRV infections, including influenza, respiratory syncytial virus, parainfluenza virus, human metapneumovirus, and adenovirus. CRV infections in cancer patients may lead to pneumonia in approximately 30% of cases, with an associated mortality of around 25%. For the diagnosis of a CRV infection, combined nasal/throat swabs or washes/aspirates yielded the best results, and nucleic acid amplification-based techniques (NAT) should be used to detect the pathogen. Hand hygiene, contact isolation, and face masks have been shown to be beneficial as general infection management. Causal treatment could be given for influenza using a neuraminidase inhibitor and for respiratory syncytial virus (RSV) using RBV in addition to IVIGs. The authors stated that RBV has also been used to treat parainfluenza virus and human metapneumovirus, but data were inconclusive in this setting.

Beaird and associates (2016) stated that the optimal treatment for RSV infection in adult immunocompromised patients is unknown. These investigators evaluated the management of RSV and other non-influenza respiratory viruses in Midwestern transplant centers. A survey assessing strategies for RSV and other non-influenza respiratory viral infections was sent to 13 centers. Multiplex polymerase chain reaction (PCR) assays were used for diagnosis in 11 of 12 centers; 8 of 12 centers used inhaled RBV in some patient populations. Barriers included cost, safety, lack of evidence, and inconvenience; 6 of 12 used IVIG, mostly in combination with RBV. Inhaled RBV was used more than oral, and in the post-stem cell transplant population, patients with LRTI, graft-versus-host disease (GVHD), and more recent transplantation were treated at higher rates. Ten centers had experience with lung transplant patients; all used either oral or inhaled RBV for LRTI, while 6 of 10 treated URTI. No center treated non-lung solid organ transplant (SOT) recipients with URTI; 7 of 11 would use oral or inhaled RBV in the same group with LRTI. Patients with hematologic malignancies without HSCT were treated with RBV at a similar frequency to non-lung SOT recipients; 3 of 12 centers, in severe cases, treated parainfluenza and metapneumovirus, and 1 of 12 treated coronavirus. The authors concluded that treatment of RSV in immunocompromised patients varied greatly. While most centers treat LRTI, treatment of URTI was variable. No consensus was found regarding the use of oral versus inhaled RBV or the use of IVIG. They stated that the presence of such heterogeneity demonstrated the need for further studies defining the optimal treatment of RSV in immunocompromised hosts.

Russell and Ison (2017) noted that PIV is a negative-sense single-stranded RNA virus in the Paramyxoviridae family. There are four serotypes that follow seasonal patterns with varying rates of infection for each serotype. PIV is an established cause of disease and death in pediatric and immunocompromised populations, and its impact on hospitalized adults is becoming more apparent with the increased use of multiplex molecular assays in the clinical setting. The clinical presentation of PIV in hospitalized adults varied widely and included URTI, severe lower respiratory tract infections (LURT), and exacerbations of underlying disease; 0.2% to 11.5% of hospitalized patients with pneumonia have been found to have PIV infection. Currently, no licensed treatment is available for PIV infection. Ribavirin has been used, but case studies showed no impact on mortality rates.

Seo and colleagues (2019) stated that PIV infection can progress from URTI to lower respiratory tract disease (LRTD) in immunocompromised hosts. Risk factors for progression to LRTD and presentation with LRTD without prior URTI are poorly defined. Recipients of HSCT with PIV infection were retrospectively analyzed using standardized definitions of LRTD; PIV was detected in 540 HCT recipients; 343 had URTI alone, and 197 (36%) had LRTD (possible, 76; probable, 19; proven, 102). Among 476 patients with positive nasopharyngeal samples, the cumulative incidence of progression to probable/proven LRTD by day 40 was 12%, with a median time to progression of 7 days (range of 2 to 40). In multivariable analysis, monocytopenia (hazard ratio [HR], 2.22; p = 0.011), steroid use of greater than or equal to 1 mg/kg prior to diagnosis (HR, 1.89; p = 0.018), co-pathogen detection in blood (HR, 3.21; p = 0.027), and PIV type 3 (HR, 3.57; p = 0.032) were associated with increased progression risk. In the absence of all four risk factors, no patients progressed to LRTD, whereas progression risk increased to greater than 30% if three or more risk factors were present. Viral load or RBV use appeared to have no effect on progression. Among 121 patients with probable/proven LRTD, 64 (53%) presented LRTD without prior URTI, and decreased lung function before infection and lower respiratory co-pathogens were risk factors for this presentation. Mortality was unaffected by the absence of prior URTI. The authors concluded that the risk of progression to probable/proven LRTD exceeded 30% with three or more risk factors. To detect all cases of LRTD, virologic testing of lower respiratory samples is needed regardless of URTI symptoms.

Smielewska and associates (2018) evaluated RBV, favipiravir (FVP), and zanamivir (ZNV) as inhibitors of minimally passaged United Kingdom clinical strains of human parainfluenza 3 (HPIV3) as well as a laboratory-adapted strain MK9 in vitro. The inhibitory action of RBV, FVP, and ZNV was evaluated against nine minimally passaged clinical strains and a laboratory-adapted strain MK9 using plaque reduction and growth curve inhibition in a cell culture model. Clinical isolates were found to be at least as susceptible as the laboratory-adapted strains to RBV and FVP and significantly more susceptible to ZNV. However, the inhibitory concentrations achieved by ZNV against clinical strains remain prohibitively high in vivo; RBV, FVP, and ZNV were found to be effective inhibitors of HPIV3 in vitro. The lack of efficacy of RBV in vivo may be due to an inability to reach required therapeutic levels; FVP, on the other hand, is a good potential therapeutic agent against HPIV3. The authors concluded that further studies using wild-type clinical strains, as well as better formulation and delivery mechanisms, may improve the utility of these three inhibitors.

Furthermore, an UpToDate review on "Parainfluenza viruses in adults" (Ison, 2018) states that "There are no antiviral agents with proven efficacy for PIV infections. We suggest not using ribavirin or intravenous immunoglobulin for the treatment of parainfluenza virus pneumonia given the lack of proven benefit."

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