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• This study measured the changes in 64 ears of 32 adult volunteers in eustachian tube function by the nine-step test, middle ear pressure by tympanometry, and nasal patency by active posterior rhinomanometry for 18 days following type 39 or Hanks rhinovirus infection. Abnormal measures were limited to the 75% of subjects (24) with clinical illness (colds) defined by symptom scores. Two days after infection, tubal function was present in only 50% of ears (48) and 20% of persons (5), middle ear underpressures of less than −50 mm H 2 O were measured in 50% of volunteers (12), and decreased nasal patency was observed in 54% of those with colds (13). These changes resolved 6 to 10 days after challenge. These results support a causal relationship between viral upper respiratory tract infection eustachian tube obstruction and abnormal middle ear pressure. ( Arch Otolaryngol Head Neck Surg. 1989;115:1054-1059)

This paper describes the longitudinal changes in nasal patency, mucociliary clearance rate, eustachian tube function, and middle ear pressure in a group of 40 volunteers infected with rhinovirus type 39. Thirty-two (80%) of the volunteers were judged to have had a cold based on the modified Jackson criteria. Common symptoms included malaise, nasal congestion, rhinorrhea, and sneezing that began on the day after challenge and peaked in intensity on days 3–5. Nasal patency evaluated by active posterior rhinomanometry and mucociliary clearance rate evaluated by the dyed sacharrin technique were significantly decreased following challenge. For nasal patency the effect was primarily limited to days 2–8 postchallenge, while abnormalities in clearance rate were documented for as long as 18 days postchallenge. A 50% increased incidence of abnormal eustachian tube function and a 30% increased incidence of abnormal middle ear pressures were observed for days 2–7 postchallenge with a gradual return to baseline by day 16. For mucociliary clearance, eustachian tube function, and middle ear pressure, but not nasal patency, these abnormalities were more pronounced in patients with a symptomatic cold. These results show that changes in nasal physiology resulting from a rhinovirus infection can be objectively quantified and that the resulting pathophysiology extends to anatomically contiguous structures such as the eustachian tube and middle ear.

We performed two studies to determine the dose-related tolerance and the efficacy of recombinant beta serine interferon (rIFN-beta ser) in experimental rhinovirus infection. In the tolerance study, 120 healthy adults received intranasal sprays of rIFN-beta ser or placebo daily for 25 d. No differences in nasal symptoms were found. Rhinoscopy detected more mucosal bleeding sites in high-dose (38%) versus low-dose (12.5%) or placebo (12.5%) recipients. There were more subepithelial lymphocytes in nasal biopsy specimens in the high-dose (54%) than the low-dose (17%) or placebo (17%) groups. In the efficacy study, 34 volunteers received daily nasal drops of IFN, beginning 36 h before challenge and for three days afterwards. The numbers of infections and days of shedding of virus were not reduced, but colds occurred less often in the high-dose (25%) than in the low-dose (55%) or placebo (64%) recipients. Nasal mucus weights were lower in the high-dose (mean +/- SD g per five days; 5 +/- 4) than placebo (31 +/- 37) recipients. Thus, rIFN-beta ser may have a more favorable therapeutic ratio than do previously tested alpha interferons.

The current study used a murine model of diabetes induced by the D variant of encephalomyocarditis virus (DEMC) to determine the protective effect of exogenous antiviral agents. Antivirals, which were found to inhibit the development of DEMC virus cytopathic effect in L-929 cell monolayers, were administered intraperitoneally beginning 12 h prior to DEMC virus challenge. Arildone (500 mg/kg per day) or murine interferon (3.2 X 10(6) IU/kg per day) significantly reduced the incidence of hyperglycemia at 4 days after virus challenge. The incidences of hyperglycemia were 96% in untreated, 62% in arildone, and 0% in interferon treated mice. In other experiments we found that interferon (1.6 X 10(6) IU/kg per 12 h X 3) significantly protected mice against diabetes when administered at the time of virus infection or beginning 12 h afterwards. This effect was associated with reductions in average viral titers in the heart and pancreas of infected animals relative to untreated, infected mice. The results of these studies suggest that picornavirus induced diabetes may be prevented or ameliorated by the use of antiviral agents.

In a double-blind, placebo-controlled study, the comparative toxicities and blood concentrations of amantadine hydrochloride and rimantadine hydrochloride were determined. Healthy, working adults ingested either 200 (n = 52) or 300 mg (n = 196) per day in divided doses for 4.5 days. Mean plasma drug concentrations at 4 h after the first dose were lower in rimantadine recipients given 100- (140 versus 300 ng/ml for rimantadine and amantadine, respectively; P less than 10(-5)) or 200-mg doses (310 versus 633 ng/ml; P less than 10(-5)). The plasma drug concentrations after the first dose correlated significantly with total symptom sources for both amantadine and rimantadine, but the plasma levels of toxic and nontoxic subjects overlapped extensively. At 300-mg/day dosage amantadine was associated more often with adverse central nervous system symptoms (33% of amantadine versus 9% of rimantadine recipients; P less than 0.001) and sleep disturbance (39 versus 13%; P less than 0.001), but not gastrointestinal symptoms (19.5 versus 16.0%). However, no differences between the drugs were noted in symptom frequency or scores in volunteers with similar plasma concentrations. Amantadine and rimantadine differ in their pharmacokinetics but not in their potential for side effects at comparable plasma concentrations.

To explore the relationship between neuraminidase immunity and the degree of attenuatíon of live influenza A virus vaccines, a comparative evaluation of three Victoria/75- ts -1[E] (Vic/75- ts -1[E]) recombinant viruses in serum hemagglutination-inhibiting-negative (titer, ≤1:8) adult volunteers was performed. These three ts -1[E] viruses had a similar restriction of replication at 38°C in vitro, and each possessed the two attenuating genes of the ts -1[E] donor strain (13). However, Vic/75- ts -1[E] recombinants 81 and 113 possessed both Vic/75 hemagglutinin (H3 75 ) and Vic/75 neuraminidase (N2 75 ), whereas Vic/75- ts -1[E] recombinant 67 had Vic/75 hemagglutinin but the N2 65 neuraminidase. Vic/75- ts -1[E] recombinant 67 was significantly more attenuated than Vic/75- ts -1[E] recombinants 81 and 113 in that fewer local and systemic signs and symptoms of illness were observed in those volunteers who received clone 67. These findings were consistent with our previous observations which suggested that the following two factors contribute to the attenuation of ts -1[E] vaccine strains in adults: (i) the attenuating effect of the two ts -1[E] genes and (ii) the neuraminidase immunity of the host. Vic/75- ts -1[E] recombinant clone 67 vaccinees developed an immunological response to the H3 75 hemagglutinin in the absence of a response to the N2 75 neuraminidase. To assess the role that anti-hemagglutinin immunity induced by an attenuated live virus vaccine plays in resistance to influenza A virus, vaccinees who received recombinant 67 were challenged with Vic/75 wild-type virus, and their responses were compared with those of Vic/75- ts -1[E] vaccinees who received recombinant 81 or 113. Each of the three groups of ts -1[E] vaccinees was significantly protected against illness induced by wild-type virus infection, although resistance was not complete. However, the clone 67 vaccinees were protected less against infection. The infection-permissive resistance induced by clone 67 resembled that previously described for inactivated neuraminidase-specific vaccines. These results suggested that a ts -1[E] recombinant that possessed the hemagglutinin of a new pandemic variant, the neuraminidase of the preceding subtype, and the two ts -1[E] ts genes would be satisfactorily attenuated for children and adults with neuraminidase immunity and could induce resistance to illness caused by the new pandemic wild-type influenza A virus.

Thirty-eight pediatric outpatients with pneumonia were studied by counterimmunoelectrophoresis for the presence of Haemophilus influenzae type b or pneumococcal antigenuria. Of the 38 patients eight (21%) hadH influenzae type b antigenuria and two (5%) had pneumococcal antigenuria. H influenzae, type b antigenuria was detected more frequently in patients

Infection of HeLa cells by human rhinoviruses (RV) of the major receptor group is inhibited by a HeLa-derived rhinovirus receptor murine monoclonal antibody (RRMA). In yield reduction studies in human embryonic lung fibroblast cells, pretreatment with 1.0 or 10 micrograms/ml of RRMA partially protected (greater than 90% titer reduction) against infection by RV 39 or coxsackie A21 (members of the major receptor family), but not by RV 1A (member of the minor receptor family). The protection afforded by RRMA persisted at least 72 h after a 2-h exposure. These results suggest that RV receptors can be effectively blocked for prolonged periods in cultured fibroblast cells.

Thirty-six adult volunteers were inoculated intranasally with 7.2 log10 egg infectious doses 50% of an attenuated A/Khabarovsk/77/H1N1 virus. Twenty-four hours later volunteers were begun on both aerosol treatments (rimantadine HCl 25 mg in saline or saline, 10 min exposure twice daily) and oral medications (rimantadine HCl 50 mg or placebo every 6 h, three times daily) which were administered for 5 days. Virus-positive volunteers receiving placebo by both of the two routes had a peak in clinical illness scores on the second treatment day (mean score 5.3), which was not observed in either the aerosol rimantadine (0.6) or oral rimantadine (0.9) treated volunteers. On the second treatment day, the proportion of virus-positive volunteers with elevated axillary temperature measurements and the mean peak temperature measurement were also significantly reduced in both drug groups. No significant effects on the duration of virus shedding were noted. In experimental influenza A virus infection, characterized by mild clinical illness and short duration of virus shedding, low doses of aerosolized rimantadine had a therapeutic effect comparable to that found with larger doses of oral rimantadine.

Intranasal recombinant interferon-alpha 2b (rIFN-alpha 2b) protects against natural colds due to rhinoviruses, but apparently not against those caused by viruses. Because rIFN-beta serine17 (rIFN-beta ser) appears less active than rIFN-alpha 2b in preventing natural rhinovirus colds, we compared the two IFNs in two in vitro assays against selected respiratory viruses. In a yield reduction assay, both IFNs had comparable activity against rhinovirus types 39 and 1A and coronavirus 229E, which were inhibited by 90% or more at IFN concentrations of 10(-11) to 10(-10) gram of protein/ml (approximately 2-20 IU/ml). Similar activities were observed with rIFN-beta ser against rhinoviruses isolated from clinical specimens. At concentrations of 10(-9) gram protein/ml, both IFNs inhibited the growth of influenza A and parainfluenza viruses, but not of adenovirus or respiratory syncytial virus in the cell culture systems tested. Thus, the different clinical protection conferred by rIFN-alpha 2b and rIFN-beta ser in studies of natural rhinovirus colds are not accounted for by differences in their in vitro activity against these viruses, and other explanations must be found.

Amantadine and rimantadine are oral antiviral drugs useful in the prophylaxis and treatment of influenza A virus infections. This article reviews the pharmacology, antiviral activity and mechanism of action, pharmacokinetics, toxicities, efficacy, and clinical applications of these agents. When administered in equivalent dosages (200 mg per day), rimantadine has prophylactic efficacy comparable to amantadine but lower potential for causing adverse effects. Despite structural similarities, these drugs differ significantly in their pharmacokinetics, and these differences may account for rimantadine's more favorable toxicity profile. Both drugs provide therapeutic benefit if administered early in uncomplicated influenza, and studies are currently in progress to determine the effectiveness of oral rimantadine in preventing or treating the serious complications of influenza A virus infections.

In a randomized, double-blind trial involving patients with uncomplicated influenza A H3N2 subtype virus infection, rimantadine treatment (200 mg/day for 5 days) was associated with significant reductions in nasal secretion viral titers (days 2 through 4), maximal temperature (days 2 and 3), time until defervescence (mean, 37 h shorter), and systemic symptoms compared with placebo treatment.

A loading dose and short-term administration of oral ribavirin significantly improved symptoms and signs of influenza type A or B infection in 25 patients. The antiviral effect was not significant. No adverse clinical effects or significant laboratory values were observed. Oral treatment of patients with influenza A or B infection might be possible with ribavirin.

Intranasal recombinant interferon-alfa2b is protective against natural rhinovirus colds when used for seasonal prophylaxis in open populations (1,2) and for postexposure prophylaxis in the family setting (3,4). However, both natural (5) and recombinant (1,2,6) alfa-interferons (IFN-α) are associated with local nasal intolerance when used for periods longer than one to two weeks. This local toxicity is manifested by complaints of nasal dryness, stuffiness, and blood-tinged mucus and rhinoscopic findings of mucosal bleeding, erosion, and ulceration. Up to one-half of adults given long-term intranasal IFN- α have experienced significant local reactions within four weeks of initiating administration (1,2,5,6). Tolerance studies of rIFN-α have found that over one-half of recipients will develop nasal histopathologic alterations, particularly subepithelial lymphocytic infiltration (7,8). This lymphocytic infiltration can occur as early as four days after initiating exposure and appears to be a precursor to the development of the clinical manifestations of local toxicity (8).

Recombinant DNA-produced human interferon-alpha 2 inhibited the replication of influenza A and B viruses in primary rhesus monkey kidney cells (RMK). Human interferon-alpha 2 interacted additively or synergistically with rimantadine hydrochloride or ribavirin in reducing the yield of clinical isolates of either H3N2 or H1N1 subtype influenza A viruses. The combination of human interferon-alpha 2 and ribavirin also inhibited the replication of an influenza B virus to a greater extent than either single agent. In addition to drug concentration, the virus inoculum and duration of culture were important variables in determining the degree of inhibition. Single drugs or combinations did not significantly inhibit the growth of uninfected RMK cells, which indicated that the observed interactions with respect to antiviral activity were not due to cell cytotoxicity.

To determine the etiology of acute conjunctivitis in children seen in pediatric practice, 99 patients with conjunctivitis and 102 age-and season-matched controls were cultured for aerobic bacteria including Haemophilus influenzae, and for viruses, Chlamydia trachomatis, and mycoplasmas. Agents statistically associated with conjunctivitis included H. influenzae (42% vs 0%), Streptococcus pneumoniae (12% vs 3%), and adenoviruses (20% vs 0%). One of these three etiologic agents was isolated from 71 (72%) of the patients. Simultaneous infection with two pathogens was uncommon. Staphylococcus aureus was equally prevalent in diseased and control eyes; one strain of C. trachomatis was isolated from a control eye. Although there were variations in the clinical features of viral and bacterial conjunctivitis, differentiation in an individual patient was difficult. An adenovirus was isolated from 11 (65%) of 17 patients who had pharyngitis in addition to conjunctivitis. H. influenzae was isolated from 14 (74%) of 19 children who had both otitis and conjunctivitis. Adenovirus conjunctivitis was common in the fall and H. influenzae in winter.

Human rhinovirus (HRV) infection can be inhibited in vitro by antibody directed against the cellular receptor for the major HRV group representing 90% of serotypes. We assessed the prophylactic effectiveness and safety of intranasally administered rhinovirus receptor murine monoclonal antibody (RRMA) in two double-blind, place-controlled, randomized studies of volunteers experimentally inoculated with HRV-39. In the first study, RRMA administration (135 μg/subject in 9 applications, −17 to +48 h) did not reduce infection (RRMA 12 15 vs. placebo 13 15 or illness ( 8 12 vs. 7 13 ) rates or modify the clinical course of experimental HRV-39 colds. In the second trial, a higher RRMA dosage (1 mg/subject in 10 applications, −3 to + 36 h), similarly did not reduce overall infection ( 11 13 vs. 12 13 ) or illness ( 7 11 vs. 9 12 ) rates, but was associated with a 1–2 day delay in the onset of viral shedding and cold symptoms and with significant reductions in viral titers and nasal symptoms on the second day after challenge and in mucus weights on the third day after challenge. No toxicity related to RRMA was recognized. The results indicate that intranasal RRMA modified infection and illness after experimental HRV-39 challenge and suggest that blockade of host cell receptors offers a novel antiviral approach against HRV infections.

The newly synthesized compound 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (MDL-860) has been found to inhibit picornavirus replication. In multiple growth cycle experiments, 1 microgram of MDL-860 per ml caused a reduction in virus yield of at least 1.0 log10 50% tissue culture infectious doses per 0.2 ml for 8 of 10 enteroviruses and 72 of 90 rhinovirus serotypes. This antiviral activity was dependent on both compound concentration and virus inoculum size. At concentrations that had no toxic effects on cell cultures, MDL-860 did not inhibit cytopathic effect or hemadsorption activity due to coronavirus 229-E, vesicular stomatitis virus, herpes simplex virus type 1, adenovirus, influenza virus A, or parainfluenza virus 1. Compound concentrations up to 25 micrograms/ml did not cause cytopathic effect in short-term cultures of rhesus monkey, WI-38, or HeLa cells; 10 micrograms/ml did not inhibit the replication of HeLa cells. The mechanism of action of MDL-860 has not been defined, although it was not directly virucidal and appeared to inhibit picornaviruses specifically at an early step in the virus-host cell interaction.

Shortly after the discovery of interferon, its broad in vitro antiviral spectrum and potential ability to be applied directly to the upper reratory tract were recognized as desirable characteristics for use in reratory viral infections (1). In 1973 Merigan et al showed that intranasal administration of human leukocyte interferon (HuIFN-α [Le]) in a total dosage of 14 Mu over 4 days reduced seroconversion and illness rates following experimental rhinovirus type 4 challenge (2). A subsequent study at the MRC Conmon Cold Unit by Scott et al utilizing a lower dosage (≥ 0.6 Mu) of fibroblast-derived interferon (IFN-β) found no evidence of protection (3). Scott et al later showed that high dosages of purified IFN-α(Le) (90 Mu over 4 days) protected against experimental rhinovirus type 9-induced illness (4). Studies conducted at Baylor College of Medicine identified rapid nasal clearance and insufficient contact time with the nasal mucosa, concentration dependency of antiviral action, and perhaps inactivation of IFN-β by nasal secretions as factors contributing to the relatively high interferon amounts needed to achieve antiviral effects in the nasal mucosa (5–9).

In late 1983, five patients living near Charlottesville, Virginia, were treated for an unusual syndrome of fever, headache, altered mentation, multifocal neurologic signs, and cerebrospinal fluid pleocytosis. Clinical signs of brainstem disease developed in four patients. All five had had recent exposure to forests or wood and contact with flea-infested dogs. Two patients died; one survivor has had recurrent seizures. Brain biopsy samples in two patients and autopsy findings in another showed cerebral vasculitis and perivasculitis involving mostly venules and capillaries. In the autopsy, the severest vascular lesions involved the brainstem and thalami, where they were accompanied by acute fibrinoid necrosis, but discrete vascular lesions of lesser intensity were randomly distributed in the white matter and cortex. Serologic studies on paired specimens in four patients showed significant cross-reacting antibody responses to rickettsial (typhus-group) antigens in the indirect hemagglutination, latex agglutination, and IgM microimmunofluorescence tests, but no agent was visualized or isolated. The cause of this serious inflammatory disorder is unknown.

• The distribution and number of lymphocytes, monocytes/macrophages, and cells expressing HLA-DR antigen were studied in frozen biopsy sections of nasal mucosa from 40 healthy adults, using monoclonal antibody avidin-biotin immunoperoxidase techniques. The lymphocyte to monocyte/macrophage ratio was estimated to be 10:1; the T cell to B cell ratio was 3:1; and the T helper/inducer cell to T suppressor/cytotoxic cell ratio averaged 2.5:1. Regional differences were observed with a relatively increased number of T suppressor/cytotoxic cells around submucosal glands, and a relatively large number of B cells in lymphocyte aggregates in the lamina propria. The HLA-DR antigen was expressed in epithelial cells, suggesting involvement of surface epithelium of human airway in local immune responses. ( Arch Otolaryngol Head Neck Surg 1987;113:59-62)

Excerpt To the editor: Anthonisen and colleagues (1) reported the effects of broad spectrum antibacterial agents in the treatment of acute exacerbations of chronic obstructive pulmonary disease. Th...

The importance of parasympathetic-cholinergic mechanisms in the production of common cold symptoms is not clear. The quaternary ammonium anticholinergic antagonist ipratropium bromide was intranasally administered under double-blind, randomized, placebo-controlled conditions to assess its tolerance and efficacy in reducing nasal hypersecretion in adult volunteers with experimental rhinovirus colds. Ipratropium was sprayed intranasally three times daily (80 micrograms per treatment) for 5 days beginning 24 h after intranasal inoculation of rhinovirus type 39. Clinical colds occurred in 50% of 30 infected ipratropium recipients and in 76% of 33 infected placebo recipients (P = 0.04). The nasal mucus weights tended to be lower for ipratropium-treated persons (mean +/- standard deviation, 14.7 +/- 15.1 g/5 days) than for placebo-treated recipients (24.7 +/- 28.0 g/5 days; P = 0.076). Whereas total nasal symptom scores were similar between the two groups, the rhinorrhea score analyzed for each day of treatment showed nonsignificant trends favoring the ipratropium group over the last 4 days of treatment. Ipratropium was generally well tolerated. The results suggest that cholinergic mechanisms are at least partially responsible for nasal mucus production in rhinovirus colds but that the effect of anticholinergic compounds alone is insufficient to be of practical use in treatment, although they may have value as components of multi-ingredient preparations.

Summary Table III summarizes clinical applications of antiviral agents in respiratory viral infections. Table IIIClinical Applications of Antiviral Agents in Respiratory Viral InfectionEffective forVirusProphylaxisTreatmentInfluenza AAmantadine (oral)Amantadine (oral)*Rimantadine (oral)Rimantadine (oral)*Ribavirin (aerosol)*Influenza BRibavirin (aerosol)*Resp. syncytialRibavirin (aerosol)RhinovirusIFN-a2 (intranasal)*Efficacy has been established only in uncomplicated disease For influenza A virus infections, both oral amantadine and rimantadine are effectvive when used for seasonal prophylaxis and for prophylaxis in institutional populations. Both of these drugs, as well as aerosilized ribavirin, have antiviral and therapeutic effects in uncomplicated influenza. It remains to be determined whether any of these modalities or possibly their combined use [44] will be useful in treating severe influenza in hospitalized patients or whether they can prevent the development of complications in high risk patients. Unfortunately, there is no parenteral formulation of amantadine or rimantadine for use in critically in patients. Aerosolized ribavirin has also been shown to have modest therapeutic effects in influenza B virus infection. However, a major need exists for an antiviral which is active against influenza B virus and which can be used on an outpatient basis. Controlled clinical trials have shown that aerosolized ribavirin therapy improves arterial oxygenation and modifies the severity fo respiratory syncytil virus bronchiolitis and pneumonia [3,5]. Its role in treatinglife-threatening disease or in dodifying the long-term sequelae of RSV infections are unknown at the present time. Again, a specific antiviral agent is needed for out-patient use in preventing or treating RSV infections. Finally, after over a decade of work since the original observation that intranasal interferon could prevent experimental rhinoirus infection [11], recent studies have established that intranasal rIFN-a2 is effective in the postexposure prophylaxis of rhinovirus colds in families [42]. This strategy needs to be studied with regard to the prevention of infection and its complications in high risk patients and it remains to be determined whether intranasal interferen will have therapeutic activity in established colds.

Annual immunization against influenza is recommended for numerous individuals, but the antibody response to sequential vaccination has not been well characterized. Levels of hemagglutination-inhibition antibody were measured in adults given either two or three doses of trivalent influenza vaccine at six-month intervals. A significant rise in the number of individuals with antibody titers of greater than or equal to 40 was seen for all three antigens only after initial vaccination. Repeated vaccination was necessary to maintain adequate antibody levels only to the A/Brazil (H1N1) antigen; it did not significantly affect the proportions of individuals with protective levels of antibody to either the A/Bangkok (H3N2) or the B/Singapore 222/79 antigens. These findings do not support the current recommendation for annual immunization when the vaccine formulation has not changed.

Cytomegalovirus (CMV) DNA was detected in a dot-blot assay by hybridization to a DNA probe labeled with radioisotopes (32P or 35S) or biotin. Limits of detection were established for both the radioisotopically labeled DNA probes as well as the biotin-labeled probe. Hybridization of the radioisotopically labeled probes was detected by autoradiography and liquid scintillation while the biotin-labeled probe was detected after coupling to one of three enzymes (e.g., horseradish peroxidase, alkaline phosphatase, or acid phosphatase). In addition, several different substrates were evaluated with the nonisotopic detection enzymes. Detection limits (and times for detection) were 1 pg (4 h) for 32P, approximately 1 pg (96 h) for 35S, 5 pg (1-3 h) for the phosphatases, and 25-50 pg for peroxidase. Thus, 32P-labeled probes appear to provide the best sensitivity whereas the avidin-linked phosphatases provide the best sensitivity among the nonisotopic detection systems.

Fifty-two healthy adults were randomly assigned interferon-alpha 2 (HuIFN-alpha 2), 8.4 X 10(6) U/day, or placebo by intranasal spray for 28 days. Symptoms, nasal examinations, and histologic analysis of nasal biopsy specimens obtained three days before and one day after exposure were evaluated under blind conditions. HuIFN-alpha 2 was associated with signs of mucosal irritation (dry mucous membranes, crusts, and friability) and/or symptoms (blood-tinged mucus) in 23% of recipients. Moderate or marked epithelial acute inflammation with ulceration occurred in 19% of HuIFN-alpha 2 recipients. Pronounced submucosal lymphocytic and mononuclear cell infiltrates developed in 58%. These histopathologic abnormalities resolved within eight weeks of stopping exposure. These results indicate that long-term or indefinite intranasal administration of HuIFN-alpha 2 at the dosages used in this study is not feasible strategy for prophylaxis of respiratory viral infections.

The role of histamine in the pathogenesis of infectious rhinitis is unclear, as is the efficacy of antihistaminic drugs in the treatment of the common cold. This study evaluated the short-term efficacy of oral terfenadine (Seldane) in the treatment of the common cold. Over a 5-week period, the authors recruited 250 adults who had developed cold symptoms within 6 to 48 hours prior to enrollment. Volunteers had a primary complaint of runny or stuffy nose; at least one other respiratory symptom; no fever or exudative pharyngitis; and no history of atopy, sinusitis, or use of cold preparations within 1 week of enrollment. Out of the eligible subjects, 126 were randomly assigned terfenadine (60 mg), and 124 received placebo. Volunteers self-administered either terfenadine or placebo twice a day on Days 1, 2 and 3, and a final dose on the morning of Day 4. They also recorded the severity of their clinical symptoms (runny nose, sniffles, sneezing, postnasal drip, cough and sore throat) on symptom cards. Both groups reported similar severity scores throughout the treatment period. Average symptom burdens declined at almost identical rates for both groups. Terfenadine was well tolerated and had a low incidence of side effects. According to subject evaluation, terfenadine was no more effective than placebo. The mean +/- SD score of global efficacy was 2.2 +/- 1.1 in the terfenadine group and 2.1 +/- 1.3 in the placebo group (P = NS). Slightly fewer terfenadine recipients (41%) than placebo recipients (48%) said they would use the study medication again for treating cold symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

The dose-related tolerance and histopathologic effects of intranasal recombinant interferon alpha-2a (rIFN-alpha 2a) were determined in a blind study in which healthy subjects were randomized to receive sprays of interferon (IFN) (3 or 6 MU/day) or placebo for 28 days. Adverse nasal symptoms (bleeding, obstruction, irritation) tended to occur more often in the IFN 6 MU/day group. Blind analysis of biopsy samples collected before and after IFN treatment revealed that both IFN groups had significant histologic changes, most commonly an increased degree of lymphocytic infiltration in the subepithelium and underlying glandular zones. Changes developed in 61% of 18 recipients of IFN 6 MU/day, 37% of 19 recipients of IFN 3 MU/day, and 6% of 18 placebo recipients. Serum antibodies to rIFN-alpha 2a detectable by EIA were found in 4 recipients of IFN 3 MU/day and 2 recipients of IFN 6 MU/day, one-third of whom were positive by neutralization bioassay. The findings would predict that these rIFN-alpha 2a dosages would be associated with an excess of adverse side effects during long-term use in healthy adults.

We conducted a randomized, placebo-controlled, double-blind study to determine whether intranasal alpha 2-interferon could prevent respiratory illnesses in healthy contacts of ill family members. Beginning within 48 hours of the onset of illness in a family member, contacts self-administered interferon (5 X 10(6) IU) or placebo spray once daily for seven days. Respiratory illness developed during the eight-day period, starting with the second day of spraying, in 52 of 222 persons in the placebo group as compared with 32 of 226 in the interferon group (P = 0.02; efficacy, 39 percent). Among persons exposed to laboratory-documented rhinovirus colds, illness developed in 2 of 27 interferon recipients as compared with 12 of 34 placebo recipients (P = 0.02; efficacy, 79 percent). During the two-week period during and after spraying, rhinovirus colds developed in 1.3 percent of those spraying with interferon and in 15.1 percent of those spraying with placebo (P = 0.003; efficacy, 88 percent). Blood-tinged mucus or nasal mucosal bleeding or both were detected in 7.7 percent of placebo and 13.6 percent of interferon users (P = 0.04), but no evidence of cumulative nasal toxicity was found. We conclude that postexposure prophylaxis with intranasal interferon may in some cases provide an effective strategy for controlling the spread of natural colds, especially those caused by rhinoviruses.

The prophylactic activity of intranasal human interferon-alpha 2 (HuIFN-alpha 2) against natural rhinovirus colds was determined in a randomized, double-blind, placebo-controlled trial. A total of 304 working adults self-administered sprays of HuIFN-alpha 2 (10(7) IU/day) or a placebo once daily. During 22 days of treatment, 13 (8.5%) placebo recipients but no HuIFN-alpha 2 recipients had respiratory illnesses documented secondary to rhinovirus infection (P = 0.0002). The occurrence of illness with symptoms of tracheobronchitis was lower in HuIFN-alpha 2 recipients (one eposide) than in placebo recipients (eight episodes, P = 0.04). In contrast, the frequency of nasal symptoms and the overall rate of respiratory illness were significantly higher in HuIFN-alpha 2 recipients during weeks 2 and 3 of treatment. Symptoms (obstruction, discomfort, blood-tinged nasal mucus) or signs (punctate bleeding sites, erosions, superficial ulcerations) of nasal irritation occurred in 40 HuIFN-alpha 2 recipients during week 3 (P less than 0.0001 versus placebo recipients). Although the results of the current study were partially confounded by the nasal side effects of prolonged administration, they showed that intranasal HuIFN-alpha 2 was efficacious in preventing rhinovirus colds under natural conditions.

The prophylactic activity of intranasal human interferon-alpha 2 (HuIFN-alpha 2) was determined in a randomized, double-blind, placebo-controlled study. Healthy, working adults self-administered sprays of HuIFN-alpha 2(1.25 X 10(6) IU; n = 142) or placebo (n = 145) twice daily. Drug administration was stopped after 12 days because of the frequent occurrence of nasal irritation manifested by blood-tinged nasal mucus (44% HuIFN-alpha 2 versus 15% placebo, P less than 0.001) and associated nasal mucosal abnormalities. Over 80% of volunteers had participated in a similar field trial conducted 7 months earlier; no evidence of cumulative toxicity was detected. HuIFN-alpha 2 administration did not decrease the occurrence of illnesses associated with rhinorrhea, cough, or feverishness as compared to placebo, but the number of laboratory-documented respiratory viral infections was small (6 HuIFN-alpha 3 placebo). Intranasal HuIFN-alpha 2 1.25 X 10(6) IU twice daily was associated with significant local intolerance.

Between September 2012 and January 20, 2017, the World Health Organization (WHO) received reports from 27 countries of 1879 laboratory-confirmed cases in humans of the Middle East respiratory syndrome (MERS) caused by infection with the MERS coronavirus (MERS-CoV) and at least 659 related deaths. Cases of MERS-CoV infection continue to occur, including sporadic zoonotic infections in humans across the Arabian Peninsula, occasional importations and associated clusters in other regions, and outbreaks of nonsustained human-to-human transmission in health care settings. Dromedary camels are considered to be the most likely source of animal-to-human transmission. MERS-CoV enters host cells after binding the dipeptidyl peptidase 4 (DPP-4) receptor and the carcinoembryonic antigen–related cell-adhesion molecule 5 (CEACAM5) cofactor ligand, and it replicates efficiently in the human respiratory epithelium. Illness begins after an incubation period of 2 to 14 days and frequently results in hypoxemic respiratory failure and the need for multiorgan support. However, asymptomatic and mild cases also occur. Real-time reverse-transcription–polymerase-chain-reaction (RT-PCR) testing of respiratory secretions is the mainstay for diagnosis, and samples from the lower respiratory tract have the greatest yield among seriously ill patients. There is no antiviral therapy of proven efficacy, and thus treatment remains largely supportive; potential vaccines are at an early developmental stage. There are multiple gaps in knowledge regarding the evolution and transmission of the virus, disease pathogenesis, treatment, and prospects for a vaccine. The ongoing occurrence of MERS in humans and the associated high mortality call for a continued collaborative approach toward gaining a better understanding of the infection both in humans and in animals.MERS-CoV was first identified in September 2012 in a patient from Saudi Arabia who had hypoxemic respiratory failure and multiorgan illness. Subsequent cases have included infections in humans across the Arabian Peninsula, occasional importations and associated clusters in other regions, and outbreaks of nonsustained human-to-human transmission in health care settings (Fig. 1).

The emerging epidemic of H5N1 avian influenza virus with spillover into the human population in Asia has provoked intense concern globally about the potential of these particularly pathogenic viruses to evolve with the capacity for human-to-human transmission with a consequent pandemic. The availability of antiviral drugs with activity against influenza A viruses and the recognition of drug-resistant variants to these drugs prompted the following report by a select group of the global experts – members of the Neuraminidase Inhibitor Susceptibility Network – on the best use of the available drugs, both for prophylaxis and treatment. The editors of Antiviral Therapyare pleased to be able to provide this document in an expeditious manner.

The single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride were compared in a randomized, two-period, crossover study involving six young (less than or equal to 35 years) and six elderly (less than or equal to 60 years) adults. Subjects ingested single 200-mg oral doses after an overnight fast, and serial plasma (0 to 96 h), nasal mucus (0 to 8 h), and urine (0 to 24 h) samples were collected for assay of drug concentration by electron capture gas chromatography. For both groups combined, rimantadine differed significantly from amantadine in peak plasma concentration (mean +/- standard deviation, 0.25 +/- 0.06 versus 0.65 +/- 0.22 micrograms/ml), plasma elimination half-life (36.5 +/- 15 versus 16.7 +/- 7.7 h), and percentage of administered dose excreted unchanged in urine (0.6 +/- 0.8 versus 45.7 +/- 15.7%). No significant age-related differences were noted for rimantadine. Urinary excretion (0 to 24 h) of rimantadine and its hydroxylated metabolites averaged 19% of the administered dose. The maximum nasal mucus drug concentration was similar for both drugs (0.42 +/- 0.25 versus 0.45 +/- 0.32 micrograms/g), and the ratio of maximum nasal mucus to plasma concentration was over twofold higher after rimantadine than after amantadine. These findings may in part explain the clinical effectiveness of rimantadine in influenza A virus infections at dosages that have lower toxicity than those of amantadine.

A previously healthy, 26-year-old heterosexual man experienced necrotic penile ulcerations with fever, rigors, and difficulty voiding. Urethral instrumentation and treatment with antibiotics were associated with progression of the disease. Type 1 herpes simplex virus was isolated from the penile ulcerations and pustular lesions in the groin and antecubital fossae. Recovery was complicated by a urethral stricture requiring surgical treatment. Herpes simplex type 1 must be considered in the differential diagnosis of severe penile ulcerations; isolation of herpesvirus from such lesions may obviate further diagnostic and therapeutic measures that are unnecessary and, in some cases, counterproductive. (JAMA1982;248:215-216)