Treatment of Persistent Rhinovirus Infection With Pegylated Interferon α2a and Ribavirin in Patients With Hypogammaglobulinemia

To The Editor—Rhinovirus (RV) is a common causative agent of acute infections. In addition to the common cold, RV infection is associated with acute otitis media, sinusitis, bronchiolitis, asthma, pneumonia, and severe infections, especially in immunocompromised patients [1]. RV infection in patients with chronic obstructive pulmonary disease may cause mortality [2]. In otherwise healthy subjects, RV shedding lasts 7–13 days [3]. No antiviral drug for RV infection is in clinical use.

We have shown that RV may induce persistent lower respiratory tract infections in patients with hypogammaglobulinemia [3, 4]. In addition, chronic RV infections have been reported in lung transplant recipients [5] and during cystic fibrosis [6]. Because RV has been observed to be susceptible to the action of interferon α [7] and because ribavirin potentiates the antiviral effect of interferon α, we treated RV infections in 4 patients who had hypogammaglobulinemia with pegylated interferon α2a and ribavirin.

Three adult patients had common variable immunodeficiency disease, and 1 adult patient had X-linked agammaglobulinemia (Table 1). Despite receipt of adequate immunoglobulin replacement therapy, they all had a history of recurrent or chronic RV infection [4]. Episodes of earlier RV infections in these patients served as self-controls during study of the duration of RV shedding after treatment. Three patients had developed bronchiectasis. At the time of treatment, all patients had respiratory symptoms. For all cases, RV was detected by culture of sputum specimens and by polymerase chain reaction analysis of nasal swab and sputum specimens. After patients provided oral informed consent, we treated them with 180 µg of pegylated interferon α2a (Pegasys, Roche, Welwyn Garden City, United Kingdom) subcutaneously once weekly and with 400 mg of ribavirin (Rebetol, MSD, Hertfordshire, United Kingdom) orally twice daily for 2 weeks.

Table 1.

Characteristics of 4 Patients With Hypogammaglobulinemia Treated With Pegylated Interferon α2a and Ribavirin

Age in y, Sex	Diagnosis, Age in y at Diagnosis	Comorbidities	Treatment	Trough Serum IgG Level, g/La	Previous RV RNA Detections, No.	RV RNA Shedding Duration in a Previous Episode, db	Treatment Date	Treated Symptom(s) of RV Infection	RV Shedding Duration Before, After Treatment	MxA Level Before, During Treatment, µg/L	Adverse Effect of Treatment	RV Negativity Duration After Ttreatment mo	New RV Episodes, Onset Date (RV Shedding Duration)
46, male	CVID, 24	ITP, AIHA, bronchiectasis, pulmonary nodules	IVIG	9.2	52	90	10 Oct 2011	Rhinorrhea	12 mo, 2 d	160, 1970	Mild flu-like symptoms	7 mo	15 Jun 2012 (8 wk), 28 Nov 2012 (5 wk)
45, male	CVID, 41	Pernicious anemia, vitiligo	SCIG	9.0	10	21	10 Nov 2012	Cough	0 wk, 3 d	20, 4710	None	2 mo	8 Jan 2013 (3 wk), 4 Oct 2013 (15 d)
59, male	CVID, 29	Pulmonary fibrosis, bronchiectasis	IVIG	7.6	25	57	23 Sep 2013	Cough, rhinorrhea	2 wk, 8 d	40, 400	Low fever	3 mo	19 Dec 2013 (5 wk)
49, male	XLA, 5	Bronchiectasis	SCIG	8.1	30	41	21 Nov 2011	Cough, rhinorrhea	6 wk, 7 d	30, 1220	Fever	6 mo	4 May 2012 (5 wk)

Abbreviations: AIHA, autoimmune hemolytic anemia; CVID, common variable immunodeficiency; IgG, immunoglobulin G; ITP, idiopathic thrombocytopenic purpura; IVIG, intravenous immunoglobulin; RV, rhinovirus; SCIG, subcutaneous immunoglobulin; XLA, X-linked agammaglobulinemia.

^a Mean trough level during a 2-year period.

^b Served as self-controls.

We found that interferon α2a and ribavirin treatment was associated with rapid decrease and clearance of RV RNA during the case episodes, compared with the self-control episodes. The efficacy of treatment was exemplified by the rapid increase of blood antiviral MxA levels (Supplementary Data) [8]. Because of chronic respiratory symptoms and concomitant use of antibiotics, the clinical outcome was difficult to adjust. However, 3 patients reported improved quality of life after treatment. Two patients reported fever as an interferon-induced adverse effect. It is of note that all 4 patients developed RV infection 2–12 months after completion of treatment. The cause of the increased susceptibility of patients with hypogammaglobulinemia to RV infection is unknown [4]. Low levels of MxA before treatment suggest deficient RV-induced interferon induction, which has been reported in subjects with asthma and chronic obstructive pulmonary disease [2]. On the other hand, exogenous interferon induced good levels of MxA, suggesting a normal IFN signaling pathway [9].

Interestingly, Falzarano et al [10] recently reported that interferon α2b and ribavirin treatment induced distinct gene expression, reduced viral replication, reduced levels of serum and lung proinflammatory markers, and improved clinical outcomes in Middle East respiratory syndrome coronavirus (MERS-CoV)–infected rhesus macaques.

Our preliminary observations in a small group of patients with primary hypogammaglobulinemia, those of Falzarano et al [10] in the treatment of MERS-CoV infection, and vast clinical experience in the treatment of chronic hepatitis C virus infection suggest that the effect of short-term pegylated interferon α and ribavirin treatment for RV infections should be studied, especially in high-risk groups.