Background Tuberculosis (TB) is increasing in the world and drug-resistant (DR) disease beckons new treatments.
Background
Tuberculosis (TB) is increasing in the world and drug-resistant (DR) disease beckons new treatments.Methods To evaluate the action of interferon (IFN) gamma as immunoadjuvant to chemotherapy on pulmonary DR-TB patients, a pilot, open label clinical trial was carried out in the Cuban reference ward for the management of this disease. The eight subjects existing in the country at the moment received, as in-patients, 1 × 10 6  IU of recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to the indicated chemotherapy, according to their antibiograms and WHO guidelines. Sputum samples collection for direct smear observation and culture as well as routine clinical and thorax radiography assessments were done monthly.
Methods
To evaluate the action of interferon (IFN) gamma as immunoadjuvant to chemotherapy on pulmonary DR-TB patients, a pilot, open label clinical trial was carried out in the Cuban reference ward for the management of this disease. The eight subjects existing in the country at the moment received, as in-patients, 1 × 10 6  IU of recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to the indicated chemotherapy, according to their antibiograms and WHO guidelines. Sputum samples collection for direct smear observation and culture as well as routine clinical and thorax radiography assessments were done monthly.Results Sputum smears and cultures became negative for acid-fast-bacilli before three months of treatment in all patients. Lesion size was reduced at the end of 6 months treatment; the lesions disappeared in one case. Clinical improvement was also evident; body mass index increased in general. Interferon gamma was well tolerated. Few adverse events were registered, mostly mild; fever and arthralgias prevailed.
Results
Sputum smears and cultures became negative for acid-fast-bacilli before three months of treatment in all patients. Lesion size was reduced at the end of 6 months treatment; the lesions disappeared in one case. Clinical improvement was also evident; body mass index increased in general. Interferon gamma was well tolerated. Few adverse events were registered, mostly mild; fever and arthralgias prevailed.Conclusions These data suggest that IFN gamma is useful and well tolerated as adjunctive therapy in patients with DR-TB. Further controlled clinical trials are encouraged.
Conclusions
These data suggest that IFN gamma is useful and well tolerated as adjunctive therapy in patients with DR-TB. Further controlled clinical trials are encouraged.

Background Tuberculosis (TB) is not yet a defeated affection. Although controllable at a community level and curable in individuals, its eradication seems distant. At present, at least one third of the World's population, more than 1 500 million individuals are infected with the  Mycobacterium tuberculosis.  Every year, around 8 – 10 million new cases occur [ 1 ]. Two million people die annually due to non-AIDS related TB, which is the highest number of deaths attributable to a single infectious agent [ 2 ], and corresponds to the 7 th  cause of death worldwide [ 3 ]. TB represents 26 % of avoidable deaths in developing countries [ 4 ]. The emergency of drug resistant (DR) or multidrug-resistant (MDR) strains has increased this global problem, leading to a high morbidity and mortality [ 5 ]. MDR-TB affected patients' mean survival ranges from 2 to 14 months [ 6 ]. According to the World Health Organization's (WHO) data, MDR patients global proportion is 2.2 % [ 7 ]. The infection is mainly transmitted by inhalation of the bacilli coming from respiratory airways infected secretions. Once inhaled, the bacilli are subjected to phagocytosis within the alveolar macrophages, where they can be destroyed. Nevertheless,  Mycobacteria  have developed mechanisms to adapt to the noxious intracellular environment. Thus, it can persist, replicate and disseminate, leading to new infectious foci. Resistance emergence depends on several factors such as initial bacillary load, inadequate or incomplete chemotherapy administration, and the patient's immune condition. Chemotherapy is successful in most cases, given that the treatment schedule is thoroughly followed. It is prolonged, costly, and needs to be directly observed. Otherwise it is inadequate to kill all the bacilli and drug resistance emerges. Toxicities are frequent as well [ 8 ]. The immunologic approach to TB treatment can be promising since only 10 – 20% of infected people develop the disease and many of them have spontaneous remission [ 9 ]. Interferon (IFN) gamma plays a main role in the immunity to TB. It is a glycoprotein, secreted by CD4+, CD8+ and NK cells. Nevertheless, CD4+ Th1 lymphocytes are the main producers in response to a stimulus [ 10 ]. Enough evidences exist related to IFN gamma action on the macrophages immunoregulatory activity [ 11 - 14 ]]. Lack of production of this cytokine [ 15 ] or expression of its receptor [ 16 , 17 ] is associated to the infection's most lethal forms. Interferon gamma has also a potent antifibrotic effect [ 18 - 20 ]. Therefore a pilot clinical study was done with the aim to evaluate IFN gamma effect on drug resistant pulmonary TB patients regarding their clinical, bacteriological and radiological evolutions. The results show that the use of this protein in eight DR-TB patients (four of them MDR) as adjuvant to antibiotics had short and middle-term beneficial effects.
Background
Tuberculosis (TB) is not yet a defeated affection. Although controllable at a community level and curable in individuals, its eradication seems distant. At present, at least one third of the World's population, more than 1 500 million individuals are infected with the  Mycobacterium tuberculosis.  Every year, around 8 – 10 million new cases occur [ 1 ]. Two million people die annually due to non-AIDS related TB, which is the highest number of deaths attributable to a single infectious agent [ 2 ], and corresponds to the 7 th  cause of death worldwide [ 3 ]. TB represents 26 % of avoidable deaths in developing countries [ 4 ]. The emergency of drug resistant (DR) or multidrug-resistant (MDR) strains has increased this global problem, leading to a high morbidity and mortality [ 5 ]. MDR-TB affected patients' mean survival ranges from 2 to 14 months [ 6 ]. According to the World Health Organization's (WHO) data, MDR patients global proportion is 2.2 % [ 7 ].Mycobacterium tuberculosis.The infection is mainly transmitted by inhalation of the bacilli coming from respiratory airways infected secretions. Once inhaled, the bacilli are subjected to phagocytosis within the alveolar macrophages, where they can be destroyed. Nevertheless,  Mycobacteria  have developed mechanisms to adapt to the noxious intracellular environment. Thus, it can persist, replicate and disseminate, leading to new infectious foci. Resistance emergence depends on several factors such as initial bacillary load, inadequate or incomplete chemotherapy administration, and the patient's immune condition.MycobacteriaChemotherapy is successful in most cases, given that the treatment schedule is thoroughly followed. It is prolonged, costly, and needs to be directly observed. Otherwise it is inadequate to kill all the bacilli and drug resistance emerges. Toxicities are frequent as well [ 8 ].The immunologic approach to TB treatment can be promising since only 10 – 20% of infected people develop the disease and many of them have spontaneous remission [ 9 ]. Interferon (IFN) gamma plays a main role in the immunity to TB. It is a glycoprotein, secreted by CD4+, CD8+ and NK cells. Nevertheless, CD4+ Th1 lymphocytes are the main producers in response to a stimulus [ 10 ].Enough evidences exist related to IFN gamma action on the macrophages immunoregulatory activity [ 11 - 14 ]]. Lack of production of this cytokine [ 15 ] or expression of its receptor [ 16 , 17 ] is associated to the infection's most lethal forms. Interferon gamma has also a potent antifibrotic effect [ 18 - 20 ].Therefore a pilot clinical study was done with the aim to evaluate IFN gamma effect on drug resistant pulmonary TB patients regarding their clinical, bacteriological and radiological evolutions. The results show that the use of this protein in eight DR-TB patients (four of them MDR) as adjuvant to antibiotics had short and middle-term beneficial effects.Methods An open-label, non-randomized, non-controlled, pilot trial was carried out at the "Benéfico -Jurídico" Hospital, Havana, which is the national reference unit for TB and other respiratory diseases. According to the national TB program, all patients with unfavorable response to treatment are remitted to this center. The study population was constituted by eight Cuban patients, both sexes, more than eighteen years old, with diagnosis of TB without a favorable response to the usual therapy, who gave their written, informed consent to participate. The diagnosis comprised clinical findings such as cough and expectoration, pulmonary lesions at thorax radiography, and positive DR-TB sputum-smear and culture. To confirm drug resistance the Canetti's multiple proportions method [ 21 ] was used as antibiogram. Exclusion criteria were another chronic disease, pregnancy or nursing, severe psychiatric dysfunction, multiple sclerosis or another autoimmune disorder, other pulmonary infections, HIV co-infection, and treatment with glucocorticoids or any other immunosuppressor medication. The previous drug therapy received by the patients included 4 drugs (isoniazid, rifampin, streptomycin, and pyrazinamide) daily during 2 months, then isoniazid and rifampin twice per week for 2 additional months. Since their sputum tests had not become negative at this point they were returned to the 4 drugs regime plus ethambutol daily for 3 months, and finally isoniazid, rifampin, and ethambutol three times per week for 5 months. The trial was done in compliance with the Helsinki Declaration. The protocol was approved by the hospital's Ethics Committee and by the Cuban Regulatory Authority. Data from nineteen historical control cases were obtained from the hospital's archives. Patients received 1 000 000 IU of human recombinant IFN gamma (Heberon Gamma R ® , Heber Biotec, Havana), intramuscularly, daily during 4 weeks and then 3 times per week for the next 20 weeks. Participants stayed as in-patients during the study period. They received anti-TB drugs (WHO schemes) [ 22 ], according to the resistance detected in each case by the antibiogram (Table  1 ). Drugs were given as follows: rifampin 10 mg/Kg (maximum 600 mg), ethambutol 20 mg/Kg (max. 1500 mg), ethionamide 10 mg/Kg (max. 750 mg), pyrazinamide 15–30 mg/Kg (max. 2000 mg), ciprofloxacin 15–20 mg/Kg (max. 1500 mg), amikacin 15 mg/Kg (max. 1000 mg), and kanamycin 15 mg/Kg (max. 1000 mg) daily. After the end of the 6-months IFN gamma treatment period, chemotherapy continued up to 9 months if the scheme included rifampin and 18 months otherwise. Evaluations were carried out at entry and monthly during IFN gamma treatment. A complete physical examination was done. Sputum samples were taken for acid-fast-bacilli smear and culture, as well as blood samples for hematological counts, globular sedimentation rate, alanine aminotransferase, and creatinin determinations. Thorax radiographies were also recorded. Afterwards, patients were followed up with half-yearly evaluations during one year. Treatment efficacy evaluation included clinical, bacteriological and radiological outcomes. Complete response was defined as total disappearance of all signs and symptoms, negative sputum acid-fast-bacilli smear and culture, and pulmonary lesions improvement at X-ray. Partial response included signs and symptoms decrease, negative sputum smear and culture and stable X-ray lesions. No response consisted in signs and symptoms persistence, positive bacteriological examinations, and lesions stabilization or progression. Safety and tolerability of the IFN gamma treatment were monitored by means of a rigorous control of the adverse events that could be presented.
Methods
An open-label, non-randomized, non-controlled, pilot trial was carried out at the "Benéfico -Jurídico" Hospital, Havana, which is the national reference unit for TB and other respiratory diseases. According to the national TB program, all patients with unfavorable response to treatment are remitted to this center.The study population was constituted by eight Cuban patients, both sexes, more than eighteen years old, with diagnosis of TB without a favorable response to the usual therapy, who gave their written, informed consent to participate. The diagnosis comprised clinical findings such as cough and expectoration, pulmonary lesions at thorax radiography, and positive DR-TB sputum-smear and culture. To confirm drug resistance the Canetti's multiple proportions method [ 21 ] was used as antibiogram. Exclusion criteria were another chronic disease, pregnancy or nursing, severe psychiatric dysfunction, multiple sclerosis or another autoimmune disorder, other pulmonary infections, HIV co-infection, and treatment with glucocorticoids or any other immunosuppressor medication.The previous drug therapy received by the patients included 4 drugs (isoniazid, rifampin, streptomycin, and pyrazinamide) daily during 2 months, then isoniazid and rifampin twice per week for 2 additional months. Since their sputum tests had not become negative at this point they were returned to the 4 drugs regime plus ethambutol daily for 3 months, and finally isoniazid, rifampin, and ethambutol three times per week for 5 months.The trial was done in compliance with the Helsinki Declaration. The protocol was approved by the hospital's Ethics Committee and by the Cuban Regulatory Authority. Data from nineteen historical control cases were obtained from the hospital's archives.Patients received 1 000 000 IU of human recombinant IFN gamma (Heberon Gamma R ® , Heber Biotec, Havana), intramuscularly, daily during 4 weeks and then 3 times per week for the next 20 weeks. Participants stayed as in-patients during the study period. They received anti-TB drugs (WHO schemes) [ 22 ], according to the resistance detected in each case by the antibiogram (Table  1 ). Drugs were given as follows: rifampin 10 mg/Kg (maximum 600 mg), ethambutol 20 mg/Kg (max. 1500 mg), ethionamide 10 mg/Kg (max. 750 mg), pyrazinamide 15–30 mg/Kg (max. 2000 mg), ciprofloxacin 15–20 mg/Kg (max. 1500 mg), amikacin 15 mg/Kg (max. 1000 mg), and kanamycin 15 mg/Kg (max. 1000 mg) daily. After the end of the 6-months IFN gamma treatment period, chemotherapy continued up to 9 months if the scheme included rifampin and 18 months otherwise.Evaluations were carried out at entry and monthly during IFN gamma treatment. A complete physical examination was done. Sputum samples were taken for acid-fast-bacilli smear and culture, as well as blood samples for hematological counts, globular sedimentation rate, alanine aminotransferase, and creatinin determinations. Thorax radiographies were also recorded. Afterwards, patients were followed up with half-yearly evaluations during one year.Treatment efficacy evaluation included clinical, bacteriological and radiological outcomes. Complete response was defined as total disappearance of all signs and symptoms, negative sputum acid-fast-bacilli smear and culture, and pulmonary lesions improvement at X-ray. Partial response included signs and symptoms decrease, negative sputum smear and culture and stable X-ray lesions. No response consisted in signs and symptoms persistence, positive bacteriological examinations, and lesions stabilization or progression. Safety and tolerability of the IFN gamma treatment were monitored by means of a rigorous control of the adverse events that could be presented.Results Eight patients were enrolled in the study. Those were all the pulmonary DR-TB cases in the country during the inclusion period, from December 1999 to February 2002. They had not responded to the usual Directly Observed Treatment Short-course (DOTS) chemotherapy regime. Strain resistance was acquired in all cases. This was well determined since in Cuba all detected cases are screened for resistance on their first isolate. The patients did not have any extra-pulmonary manifestation of the disease. Their demographic and baseline characteristics are shown in Table  1 . Five of them were men, six of them non-white. The age ranged between 23 and 54 years old, and body mass index (BMI) between 13.2 and 22.0 Kg/m 2 . Their main symptoms were cough, expectorations, dyspnea, stertors, distal cyanosis, and finger clubbing. Bacteriological tests codification was mostly high and all patients showed active lesions at thorax radiography. Most of them had accelerated globular sedimentation rates (GSR). Anemia or other hematological alterations were not recorded. A rapid favorable evolution was obtained after treatment with IFN gamma (Table  2 ). Clinical improvement was evident since the first month of treatment, when all signs and symptoms (except for finger clubbing) had disappeared in all patients and BMI increased in all but one of them. Sputum acid-fast-bacilli smears and cultures were negative since the 1 – 3 months of treatment. The eight patients had radiological improvement, with lesions size reduction (total disappearance in one case) (Figure  1 ). GSR decreased in five out of 6 patients who had abnormal values at inclusion. After six additional months follow-up, patients # 3 and 4 normalized it to 10 and 15 mm/h, respectively. At the end of the IFN gamma treatment all the patients were evaluated as complete responders. The treatment with IFN gamma was safe and well tolerated. Four patients presented at least one adverse event. These events were arthralgias, fever, headache and asthenia. All adverse events were mild, except for one moderate fever, which was efficiently controlled with acetaminophen. Significant differences were not detected in other clinical laboratory tests. After completion or the IFN gamma 6-months treatment the patients continued with the corresponding chemotherapy schedule. Seven of the eight patients remained bacteriologically, clinically and radiologically negative at least twelve months after the treatment with IFN gamma concluded. However, patient number five relapsed six months after the end of IFN therapy. He developed additional resistance to rifampin and ethionamide and a chronic obstructive respiratory disease that contributed negatively to his evolution. Table  3  shows the results obtained at the same hospital with the 19 DR-TB cases during the five years prior to the present study. These patients had also failed to the standard DOTS regime. They were all resistant to isoniazid and rifampin, 13 were resistant to streptomycin, 7 to kanamycin, 4 to ethambutol, and one to pyrazinamide. Resistance was primary in 2 cases and acquired in the rest. Their average age was 58 years. Management was essentially the same as for the patients included in the study, except for IFN gamma treatment. None of these DR-TB cases reached culture conversion at three months of treatment with chemotherapy and less than half had converted at six months. Their clinical outcome was also worse.
Results
Eight patients were enrolled in the study. Those were all the pulmonary DR-TB cases in the country during the inclusion period, from December 1999 to February 2002. They had not responded to the usual Directly Observed Treatment Short-course (DOTS) chemotherapy regime. Strain resistance was acquired in all cases. This was well determined since in Cuba all detected cases are screened for resistance on their first isolate. The patients did not have any extra-pulmonary manifestation of the disease. Their demographic and baseline characteristics are shown in Table  1 . Five of them were men, six of them non-white. The age ranged between 23 and 54 years old, and body mass index (BMI) between 13.2 and 22.0 Kg/m 2 . Their main symptoms were cough, expectorations, dyspnea, stertors, distal cyanosis, and finger clubbing. Bacteriological tests codification was mostly high and all patients showed active lesions at thorax radiography. Most of them had accelerated globular sedimentation rates (GSR). Anemia or other hematological alterations were not recorded.A rapid favorable evolution was obtained after treatment with IFN gamma (Table  2 ). Clinical improvement was evident since the first month of treatment, when all signs and symptoms (except for finger clubbing) had disappeared in all patients and BMI increased in all but one of them. Sputum acid-fast-bacilli smears and cultures were negative since the 1 – 3 months of treatment. The eight patients had radiological improvement, with lesions size reduction (total disappearance in one case) (Figure  1 ). GSR decreased in five out of 6 patients who had abnormal values at inclusion. After six additional months follow-up, patients # 3 and 4 normalized it to 10 and 15 mm/h, respectively. At the end of the IFN gamma treatment all the patients were evaluated as complete responders.The treatment with IFN gamma was safe and well tolerated. Four patients presented at least one adverse event. These events were arthralgias, fever, headache and asthenia. All adverse events were mild, except for one moderate fever, which was efficiently controlled with acetaminophen. Significant differences were not detected in other clinical laboratory tests.After completion or the IFN gamma 6-months treatment the patients continued with the corresponding chemotherapy schedule. Seven of the eight patients remained bacteriologically, clinically and radiologically negative at least twelve months after the treatment with IFN gamma concluded. However, patient number five relapsed six months after the end of IFN therapy. He developed additional resistance to rifampin and ethionamide and a chronic obstructive respiratory disease that contributed negatively to his evolution.Table  3  shows the results obtained at the same hospital with the 19 DR-TB cases during the five years prior to the present study. These patients had also failed to the standard DOTS regime. They were all resistant to isoniazid and rifampin, 13 were resistant to streptomycin, 7 to kanamycin, 4 to ethambutol, and one to pyrazinamide. Resistance was primary in 2 cases and acquired in the rest. Their average age was 58 years. Management was essentially the same as for the patients included in the study, except for IFN gamma treatment. None of these DR-TB cases reached culture conversion at three months of treatment with chemotherapy and less than half had converted at six months. Their clinical outcome was also worse.Discussion In spite of the reduced size of the population studied, the results suggest the efficacy of IFN gamma on DR-TB, when used as adjuvant to chemotherapy. All eight patients were considered as complete responders at the end of IFN treatment with disappearance of the disease signs and symptoms, sputum tests conversion, and pulmonary lesions improvement. Bacteriological and radiological improvement correlated with the clinical evolution; BMI increased and manifestations as cough and expectoration did not recur after IFN gamma treatment. Clinical practice demonstrates that these results are very difficult to obtain in such a short period of time with the chemotherapy alone. Any conclusion from this study is also limited by the fact that it was not a controlled trial. This was not possible due to the low incidence of TB (7.6/100,000 inhabitants in 2002) [ 23 ] and DR-TB in Cuba [ 7 ]. Therefore a historical control with the results obtained at the same hospital by the same investigators in patients treated only with chemotherapy is used for comparison. Despite the fact that this kind of control is not fully comparable since they were not in the original design of the trial, a clear difference is shown regarding patients' performance. Literature reports on chemotherapy-treated DR-TB patients show similar unfavorable outcome [ 6 ]. The fact that four patients received rifampin, according to the strain sensitivity, which is one of the election drugs for the treatment of TB with excellent results in patients treated with DOTS regime, does not diminish the consideration regarding the possible benefit exerted by IFN gamma since these same patients had already not responded to this antibiotic as part of the DOTS. Moreover, one patient recurred after he had finished IFN gamma treatment for 6 months, despite still being under chemotherapy regime. This suggests that in his case a new IFN gamma cycle combined to the antibiotics would have been necessary, but this was not previewed in the protocol. However, only a controlled trial can definitely clarify the role of IFN gamma and second line antibiotics in this kind of patient's improvement. The radiological results demonstrated IFN gamma antifibrotic properties as well. All patients had a reduction in the pulmonary lesions size, while one showed a complete resolution. This effect cannot be attributable to the antibiotics, since it is well known that DR-TB patients only develop radiological improvement long time after sputum smears and culture become negative. In many cases extensive fibrotic lesions never improve, and stay stable for life. This antifibrotic action agrees with that obtained with IFN gamma in idiopathic lung fibrosis [ 24 ] and suggests that IFN gamma can have future indications in other pulmonary diseases where fibrosis is present. Therapy was well tolerated. It was not necessary to suspend the combined treatment due to adverse events; mostly mild. Adverse events such as arthralgias, fever and headache coincide with those reported for interferons [ 25 ]. Immunity to TB depends on the development of CD4+ cells- and macrophages-mediated Th1 response. The role of IFN gamma as the main macrophage-activator Th1 cytokine has been clearly established in animal models infected with  M. tuberculosis  [ 15 , 26 , 27 ]. IFN gamma action on the macrophages leads to kill intracellular  Mycobacteria . It stimulates macrophages to produce tumor necrosis factor alpha (TNF α), oxygen free radicals and nitric oxide, increase surface display of MHC antigens and Fc receptors, decrease lysosomal pH, and increase the intracellular concentration of some antibiotics [ 11 - 14 , 28 ]. Regarding its antifibrotic effect, IFN gamma inhibits lung fibroblast proliferation and chemotaxis in a dose dependent manner, and reduces collagen synthesis [ 18 , 19 , 29 ]. Furthermore, this protein is a potent inhibitor of the transforming growth factor β (TGF-β)[ 20 ], involved in the pathogenesis of many fibrotic lung diseases [ 30 - 32 ]. On the other hand, mutations in the IFN gamma gene [ 15 ], or in the IFN gamma receptor alpha chain gene [ 16 , 17 ], increase susceptibility to develop the disease. Patients with disseminated BCG and other infections present defects in IFN gamma and other cytokines secretion and action [ 33 - 35 ]. IFN gamma therapy has been shown effective for cerebral tuberculosis caused by a multidrug-resistant strain [ 36 ]. The aerosol route of administration has been proposed as organ specific delivery method, obtaining a high release to infected alveoli [ 37 ]. Condos et al. reported clinical and bacteriological improvement and tolerability with aerosolized IFN gamma in five patients with MDR-TB [ 38 ]. In addition, other previous trials demonstrated promising results in patients infected with other  Mycobacteria  [ 10 , 39 - 42 ].
Discussion
In spite of the reduced size of the population studied, the results suggest the efficacy of IFN gamma on DR-TB, when used as adjuvant to chemotherapy. All eight patients were considered as complete responders at the end of IFN treatment with disappearance of the disease signs and symptoms, sputum tests conversion, and pulmonary lesions improvement. Bacteriological and radiological improvement correlated with the clinical evolution; BMI increased and manifestations as cough and expectoration did not recur after IFN gamma treatment. Clinical practice demonstrates that these results are very difficult to obtain in such a short period of time with the chemotherapy alone.Any conclusion from this study is also limited by the fact that it was not a controlled trial. This was not possible due to the low incidence of TB (7.6/100,000 inhabitants in 2002) [ 23 ] and DR-TB in Cuba [ 7 ]. Therefore a historical control with the results obtained at the same hospital by the same investigators in patients treated only with chemotherapy is used for comparison. Despite the fact that this kind of control is not fully comparable since they were not in the original design of the trial, a clear difference is shown regarding patients' performance. Literature reports on chemotherapy-treated DR-TB patients show similar unfavorable outcome [ 6 ].The fact that four patients received rifampin, according to the strain sensitivity, which is one of the election drugs for the treatment of TB with excellent results in patients treated with DOTS regime, does not diminish the consideration regarding the possible benefit exerted by IFN gamma since these same patients had already not responded to this antibiotic as part of the DOTS. Moreover, one patient recurred after he had finished IFN gamma treatment for 6 months, despite still being under chemotherapy regime. This suggests that in his case a new IFN gamma cycle combined to the antibiotics would have been necessary, but this was not previewed in the protocol. However, only a controlled trial can definitely clarify the role of IFN gamma and second line antibiotics in this kind of patient's improvement.The radiological results demonstrated IFN gamma antifibrotic properties as well. All patients had a reduction in the pulmonary lesions size, while one showed a complete resolution. This effect cannot be attributable to the antibiotics, since it is well known that DR-TB patients only develop radiological improvement long time after sputum smears and culture become negative. In many cases extensive fibrotic lesions never improve, and stay stable for life. This antifibrotic action agrees with that obtained with IFN gamma in idiopathic lung fibrosis [ 24 ] and suggests that IFN gamma can have future indications in other pulmonary diseases where fibrosis is present.Therapy was well tolerated. It was not necessary to suspend the combined treatment due to adverse events; mostly mild. Adverse events such as arthralgias, fever and headache coincide with those reported for interferons [ 25 ].Immunity to TB depends on the development of CD4+ cells- and macrophages-mediated Th1 response. The role of IFN gamma as the main macrophage-activator Th1 cytokine has been clearly established in animal models infected with  M. tuberculosis  [ 15 , 26 , 27 ]. IFN gamma action on the macrophages leads to kill intracellular  Mycobacteria . It stimulates macrophages to produce tumor necrosis factor alpha (TNF α), oxygen free radicals and nitric oxide, increase surface display of MHC antigens and Fc receptors, decrease lysosomal pH, and increase the intracellular concentration of some antibiotics [ 11 - 14 , 28 ].M. tuberculosisMycobacteriaRegarding its antifibrotic effect, IFN gamma inhibits lung fibroblast proliferation and chemotaxis in a dose dependent manner, and reduces collagen synthesis [ 18 , 19 , 29 ]. Furthermore, this protein is a potent inhibitor of the transforming growth factor β (TGF-β)[ 20 ], involved in the pathogenesis of many fibrotic lung diseases [ 30 - 32 ].On the other hand, mutations in the IFN gamma gene [ 15 ], or in the IFN gamma receptor alpha chain gene [ 16 , 17 ], increase susceptibility to develop the disease. Patients with disseminated BCG and other infections present defects in IFN gamma and other cytokines secretion and action [ 33 - 35 ].IFN gamma therapy has been shown effective for cerebral tuberculosis caused by a multidrug-resistant strain [ 36 ]. The aerosol route of administration has been proposed as organ specific delivery method, obtaining a high release to infected alveoli [ 37 ]. Condos et al. reported clinical and bacteriological improvement and tolerability with aerosolized IFN gamma in five patients with MDR-TB [ 38 ]. In addition, other previous trials demonstrated promising results in patients infected with other  Mycobacteria  [ 10 , 39 - 42 ].MycobacteriaConclusions These results can suggest a beneficial effect of IFN gamma when it is used as adjuvant in the treatment of tuberculosis patients that have resistance to standard chemotherapy, and encourage carrying out more extensive, controlled studies. Combination with second-line drugs can reduce the time of treatment, diminishing toxicities and possible relapses; in many cases could reduce the application of recessional surgery. Further controlled clinical trials are needed to confirm these results.
Conclusions
These results can suggest a beneficial effect of IFN gamma when it is used as adjuvant in the treatment of tuberculosis patients that have resistance to standard chemotherapy, and encourage carrying out more extensive, controlled studies. Combination with second-line drugs can reduce the time of treatment, diminishing toxicities and possible relapses; in many cases could reduce the application of recessional surgery. Further controlled clinical trials are needed to confirm these results.Competing interests Authors IGG, CMVS, and PALS are employees of the Center for Biological Research, which is part of the Center for Genetic Engineering and Biotechnology, Havana network, where IFN gamma is produced. The rest of the authors have no competing interests at all.
Competing interests
Authors IGG, CMVS, and PALS are employees of the Center for Biological Research, which is part of the Center for Genetic Engineering and Biotechnology, Havana network, where IFN gamma is produced. The rest of the authors have no competing interests at all.Authors' contributions RSM conceived the study and carried out the bacteriological determinations. IGG participated in the study design and coordinating, and wrote the manuscript draft. NFO, MVQ, MTM, DC, and DMM took care of patient recruitment, management, and follow-up. CMVS participated in the study design and result analysis. PALS took part in the design, results analysis and manuscript writing. All authors read and approved the final manuscript.
Authors' contributions
RSM conceived the study and carried out the bacteriological determinations. IGG participated in the study design and coordinating, and wrote the manuscript draft. NFO, MVQ, MTM, DC, and DMM took care of patient recruitment, management, and follow-up. CMVS participated in the study design and result analysis. PALS took part in the design, results analysis and manuscript writing. All authors read and approved the final manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here:


Background Parental smoking and prone sleep positioning are recognized causal features of Sudden Infant Death. This study quantifies the relationship between prenatal smoking and infant death over the time period of the  Back to Sleep  campaign in the United States, which encouraged parents to use a supine sleeping position for infants.
Background
Parental smoking and prone sleep positioning are recognized causal features of Sudden Infant Death. This study quantifies the relationship between prenatal smoking and infant death over the time period of the  Back to Sleep  campaign in the United States, which encouraged parents to use a supine sleeping position for infants.Back to SleepMethods This retrospective cohort study utilized the Colorado Birth Registry. All singleton, normal birth weight infants born from 1989 to 1998 were identified and linked to the Colorado Infant Death registry. Multivariable logistic regression was used to analyze the relationship between outcomes of interest and prenatal maternal cigarette use. Potential confounders analyzed included infant gender, gestational age, and birth year as well as maternal marital status, ethnicity, pregnancy interval, age, education, and alcohol use.
Methods
This retrospective cohort study utilized the Colorado Birth Registry. All singleton, normal birth weight infants born from 1989 to 1998 were identified and linked to the Colorado Infant Death registry. Multivariable logistic regression was used to analyze the relationship between outcomes of interest and prenatal maternal cigarette use. Potential confounders analyzed included infant gender, gestational age, and birth year as well as maternal marital status, ethnicity, pregnancy interval, age, education, and alcohol use.Results We analyzed 488,918 birth records after excluding 5835 records with missing smoking status. Smokers were more likely to be single, non-Hispanic, less educated, and to report alcohol use while pregnant (p < 0.001). The study included 598 SIDS cases of which 172 occurred in smoke-exposed infants. Smoke exposed infants were 1.9 times (95% CI 1.6 to 2.3) more likely to die of SIDS. The attributed risk associating smoking and SIDS increased during the study period from approximately 50% to 80%. During the entire study period 59% (101/172) of SIDS deaths in smoke-exposed infants were attributed to maternal smoking.
Results
We analyzed 488,918 birth records after excluding 5835 records with missing smoking status. Smokers were more likely to be single, non-Hispanic, less educated, and to report alcohol use while pregnant (p < 0.001). The study included 598 SIDS cases of which 172 occurred in smoke-exposed infants. Smoke exposed infants were 1.9 times (95% CI 1.6 to 2.3) more likely to die of SIDS. The attributed risk associating smoking and SIDS increased during the study period from approximately 50% to 80%. During the entire study period 59% (101/172) of SIDS deaths in smoke-exposed infants were attributed to maternal smoking.Conclusions Due to a decreased overall rate of SIDS likely due to changing infant sleep position, the attributed risk associating maternal smoking and SIDS has increased following the  Back to Sleep  campaign. Mothers should be informed of the 2-fold increased rate of SIDS associated with maternal cigarette consumption.
Conclusions
Due to a decreased overall rate of SIDS likely due to changing infant sleep position, the attributed risk associating maternal smoking and SIDS has increased following the  Back to Sleep  campaign. Mothers should be informed of the 2-fold increased rate of SIDS associated with maternal cigarette consumption.Back to Sleep

Background Previous literature has shown a relationship between maternal smoking and the Sudden Infant Death Syndrome (SIDS). Published studies vary in size and methodology but consistently demonstrate a two-fold increased odds of SIDS with both prenatal and postnatal maternal smoking [ 1 - 10 ], including one study of over 300,000 infants in an analysis of birth registry data from the late 1970s [ 4 , 6 ]. A recent secular change, namely the  Back to Sleep  campaign, has had a major role in reducing SIDS rates. This public health campaign encourages parents to place infants in a supine rather than prone sleeping position. Early studies investigating the effects of supine sleeping revealed significantly reduced SIDS rates [ 11 ], but smoking among mothers, which was not targeted as the primary intervention, remained unchanged. The aim of this study was to confirm the relationship between reported prenatal maternal smoking and SIDS and to examine the effect of sleeping position changes on the attributed risk of SIDS and smoking. The analysis spans the rollout of the  Back to Sleep  campaign in the United States for the ten-year period from 1989 to 1998. We hypothesized that maternal prenatal smoking confers a clinically significant risk of SIDS and that an increased attributed risk of SIDS associated with smoking could be identified in the wake of the supine sleeping campaign.
Background
Previous literature has shown a relationship between maternal smoking and the Sudden Infant Death Syndrome (SIDS). Published studies vary in size and methodology but consistently demonstrate a two-fold increased odds of SIDS with both prenatal and postnatal maternal smoking [ 1 - 10 ], including one study of over 300,000 infants in an analysis of birth registry data from the late 1970s [ 4 , 6 ]. A recent secular change, namely the  Back to Sleep  campaign, has had a major role in reducing SIDS rates. This public health campaign encourages parents to place infants in a supine rather than prone sleeping position. Early studies investigating the effects of supine sleeping revealed significantly reduced SIDS rates [ 11 ], but smoking among mothers, which was not targeted as the primary intervention, remained unchanged.Back to SleepThe aim of this study was to confirm the relationship between reported prenatal maternal smoking and SIDS and to examine the effect of sleeping position changes on the attributed risk of SIDS and smoking. The analysis spans the rollout of the  Back to Sleep  campaign in the United States for the ten-year period from 1989 to 1998. We hypothesized that maternal prenatal smoking confers a clinically significant risk of SIDS and that an increased attributed risk of SIDS associated with smoking could be identified in the wake of the supine sleeping campaign.Back to SleepMethods Study setting/population Since 1969, the State of Colorado has collected data on multiple items through a birth registry. This registry includes extensive demographic data such as maternal report of the number of cigarettes smoked per day during pregnancy. We used the Colorado Infant Death Registry over a 10-year period (1989–1998) to identify causes of infant death. Study design We conducted a retrospective cohort study utilizing Cochran Mantel-Haenszel univariate analysis of risk factors and multiple logistic regression on the outcomes of infant death, SIDS, and respiratory deaths. We excluded non-singleton births (14978 records), infants born at less than 2500 grams (36779 records), and birth records where a mother's smoking status was unknown (5835 records). Additional records with missing data were coded so as to place the record in the presumed lower risk group: 42 records with unclear marital status were coded as "married," 67 records missing a maternal age were coded as age "18–34 years," 865 records with unclear gestational age were coded as "term" infants, and 4 records missing a gender assignment were coded as "female" in the analysis. Missing data for education (9659 records) and ethnicity (582 records) were coded as such and included in the analysis directly. We linked the birth and death registries using a unique birth number present in both registries. Utilizing multiple logistic regression, we modeled the exposure of interest, maternal smoking, as both a dichotomous and a continuous variable. Other variables analyzed included infant gender and gestational age (less than 37 weeks, 37 weeks or older), as well as maternal marital status, ethnicity, time between pregnancies (less than 12 months or 12 months and greater), maternal age (<18 years, 18 to 34 years, and >34 years), education, and self-reported use of alcohol in pregnancy. In the analyses for SIDS and respiratory causes of death, deaths from other causes were excluded from the analysis. Power to detect a 20% difference in a baseline disease occurrence of 3 per 1000 was calculated at 99% for a population of 500,000. SAS version 8.0 (SAS Institute) on a PC was utilized for statistical analyses. We included the interaction between ethnicity and cigarette use in the modeling and requested the Hosmer-Lemeshow statistic from the model. Study outcomes We compared cases of SIDS (ICD 9 codes 798.0 to 798.9) between cohorts of infants born to mothers who reported prenatal smoking versus mothers who reported no prenatal smoking. Secondary outcomes included total infant mortality and respiratory deaths (ICD 9 codes 033.0 to 033.9 and 460 to 490). We used unadjusted annual rates to calculate the attributable risk of SIDS associated with maternal cigarette consumption.
Methods
Study setting/population Since 1969, the State of Colorado has collected data on multiple items through a birth registry. This registry includes extensive demographic data such as maternal report of the number of cigarettes smoked per day during pregnancy. We used the Colorado Infant Death Registry over a 10-year period (1989–1998) to identify causes of infant death.
Study setting/population
Since 1969, the State of Colorado has collected data on multiple items through a birth registry. This registry includes extensive demographic data such as maternal report of the number of cigarettes smoked per day during pregnancy. We used the Colorado Infant Death Registry over a 10-year period (1989–1998) to identify causes of infant death.Study design We conducted a retrospective cohort study utilizing Cochran Mantel-Haenszel univariate analysis of risk factors and multiple logistic regression on the outcomes of infant death, SIDS, and respiratory deaths. We excluded non-singleton births (14978 records), infants born at less than 2500 grams (36779 records), and birth records where a mother's smoking status was unknown (5835 records). Additional records with missing data were coded so as to place the record in the presumed lower risk group: 42 records with unclear marital status were coded as "married," 67 records missing a maternal age were coded as age "18–34 years," 865 records with unclear gestational age were coded as "term" infants, and 4 records missing a gender assignment were coded as "female" in the analysis. Missing data for education (9659 records) and ethnicity (582 records) were coded as such and included in the analysis directly. We linked the birth and death registries using a unique birth number present in both registries. Utilizing multiple logistic regression, we modeled the exposure of interest, maternal smoking, as both a dichotomous and a continuous variable. Other variables analyzed included infant gender and gestational age (less than 37 weeks, 37 weeks or older), as well as maternal marital status, ethnicity, time between pregnancies (less than 12 months or 12 months and greater), maternal age (<18 years, 18 to 34 years, and >34 years), education, and self-reported use of alcohol in pregnancy. In the analyses for SIDS and respiratory causes of death, deaths from other causes were excluded from the analysis. Power to detect a 20% difference in a baseline disease occurrence of 3 per 1000 was calculated at 99% for a population of 500,000. SAS version 8.0 (SAS Institute) on a PC was utilized for statistical analyses. We included the interaction between ethnicity and cigarette use in the modeling and requested the Hosmer-Lemeshow statistic from the model.
Study design
We conducted a retrospective cohort study utilizing Cochran Mantel-Haenszel univariate analysis of risk factors and multiple logistic regression on the outcomes of infant death, SIDS, and respiratory deaths. We excluded non-singleton births (14978 records), infants born at less than 2500 grams (36779 records), and birth records where a mother's smoking status was unknown (5835 records). Additional records with missing data were coded so as to place the record in the presumed lower risk group: 42 records with unclear marital status were coded as "married," 67 records missing a maternal age were coded as age "18–34 years," 865 records with unclear gestational age were coded as "term" infants, and 4 records missing a gender assignment were coded as "female" in the analysis. Missing data for education (9659 records) and ethnicity (582 records) were coded as such and included in the analysis directly. We linked the birth and death registries using a unique birth number present in both registries. Utilizing multiple logistic regression, we modeled the exposure of interest, maternal smoking, as both a dichotomous and a continuous variable. Other variables analyzed included infant gender and gestational age (less than 37 weeks, 37 weeks or older), as well as maternal marital status, ethnicity, time between pregnancies (less than 12 months or 12 months and greater), maternal age (<18 years, 18 to 34 years, and >34 years), education, and self-reported use of alcohol in pregnancy. In the analyses for SIDS and respiratory causes of death, deaths from other causes were excluded from the analysis.Power to detect a 20% difference in a baseline disease occurrence of 3 per 1000 was calculated at 99% for a population of 500,000. SAS version 8.0 (SAS Institute) on a PC was utilized for statistical analyses. We included the interaction between ethnicity and cigarette use in the modeling and requested the Hosmer-Lemeshow statistic from the model.Study outcomes We compared cases of SIDS (ICD 9 codes 798.0 to 798.9) between cohorts of infants born to mothers who reported prenatal smoking versus mothers who reported no prenatal smoking. Secondary outcomes included total infant mortality and respiratory deaths (ICD 9 codes 033.0 to 033.9 and 460 to 490). We used unadjusted annual rates to calculate the attributable risk of SIDS associated with maternal cigarette consumption.
Study outcomes
We compared cases of SIDS (ICD 9 codes 798.0 to 798.9) between cohorts of infants born to mothers who reported prenatal smoking versus mothers who reported no prenatal smoking. Secondary outcomes included total infant mortality and respiratory deaths (ICD 9 codes 033.0 to 033.9 and 460 to 490). We used unadjusted annual rates to calculate the attributable risk of SIDS associated with maternal cigarette consumption.Results Over the 10-year study period, 1573 infants died, 598 SIDS cases occurred (1.2/1000 live born infants), and 34 infants died due to a respiratory etiology. Table  1  describes characteristics of the exposed and unexposed infant cohorts. Smoking mothers were statistically more likely to be single, non-Hispanic, less educated, and to report alcohol use in pregnancy. Table 1 Demographic characteristics of 488,918 births according to maternal smoking habits during pregnancy, Colorado Birth Registry, 1989 to 1998. Number (%) Reported maternal smoking (%) Sex male 252,066 (51.6) 13.4 female 236,852 (48.4) 13.1 Gestational age <37 weeks 16,057 (3.3) 14.7 "term" 472,861 (96.7) 13.2 Marital status of mother married 376,222 (77.0) 10.1 single 112,696 (23.0) 23.9 Time between births 12 months or less 19,987 (4.1) 16.0 >12 months 468,931 (95.9) 13.2 Maternal Age 17 years or less 21,362 (4.4) 17.1 18 to 34 years 407,801 (83.4) 13.7 35 years or more 59,755 (12.2) 8.9 Maternal Ethnicity caucasian 351,051 (71.8) 14.3 hispanic 97,911 (20.0) 10.4 black 21,989 (4.5) 14.4 other/missing 17,967 (3.7) 8.5 Maternal Educational level <high school 85,284 (17.4) 23.9 high school 157,852 (32.3) 17.9 some college 111,824 (22.9) 10.5 college 112,384 (23.0) 3.0 more than college 13,840 (2.8) 1.7 missing 7734 (1.6) 12.5 Maternal Alcohol use none 477,733 (97.7) 12.6 1 to 50 drinks/week 11,185 (2.3) 42.8 We calculated adjusted odds ratios by analyzing smoking as a dichotomous exposure (mother smoked or did not smoke) and as a continuous variable (number of reported cigarettes per day during the pregnancy). Dichotomous outcomes of reported smoking during pregnancy yielded adjusted odds ratios of 1.9 (95% CI: 1.6 to 2.3) for death due to SIDS, 1.5 (95% CI: 1.3 to 1.7) for infant deaths from all causes, and 3.0 (95% CI: 1.4 to 6.3) for deaths due to respiratory etiologies (p < 0.01 for all outcomes). Table  2  shows results for the model for each of the outcomes. The final logistic regression model for each outcome was slightly different, but smoking remained in each as a significant factor. The interaction between ethnicity and cigarette use did not contribute significantly to the final model and thus was excluded. Table 2 Adjusted odds ratios for SIDS, all infant deaths, and respiratory deaths with dichotomous cigarette use and other potential confounders* SIDS p All deaths p Respiratory deaths p Reported smoking <0.0001 0.0001 0.0032  No cigarette use 1.0 1.0 1.0  Cigarette use 1.9 1.5 3.0 Gender <0.0001 <0.0001 Not significant  Female 1.0 1.0  Male 2.0 1.4 Marital status <0.0001 <0.0001 0.0127  Married 1.0 1.0 1.0  Not married 1.7 1.5 2.5 Pregnancy interval 0.0033 0.0016 0.0056  12 months or more 1.0 1.0 1.0  Less than 12 mo. 1.6 1.4 3.8 Gestational age 0.0053 <0.0001 Not significant  Term 1.0 1.0  Less than 37 weeks 1.6 3.7 Any alcohol use Not significant Not significant Not significant Education 0.0002 <0.0001 Not significant  More than college 1.0 1.0  College 0.6 1.0  Some college 0.9 1.2  High school 0.9 1.2  Some high school 1.3 1.4  Unknown 0.7 2.1 Ethnicity 0.0204 Not significant 0.0337  White 1.0 1.0  Hispanic 0.8 1.8  Black 1.4 0.6  Other 0.7 4.5 Year of birth <0.0001 <0.0001 Not significant  1998 1.0 1.0  1997 1.7 1.0  1996 1.7 0.8  1995 1.6 0.8  1994 1.7 0.9  1993 2.7 1.0  1992 3.0 1.1  1991 3.6 1.3  1990 3.0 1.3  1989 3.1 1.4 *Logistic regression modelling with corresponding p-values for each variable Analyzing cigarette consumption as a continuous variable shows the associated odds  per cigarette  are 1.042 (95% CI: 1.030 to 1.054; p < 0.0001). In this model, consumption of 10 cigarettes per day is associated with a 51% increased odds of SIDS (95% risk limit 35% to 70%). The Hosmer-Lemeshow test statistic was non-significant (p > 0.1948) suggesting adequate model fit. Table  3  shows crude rates of SIDS in the exposed and unexposed cohorts of infants for the years 1989 to 1998. Included is a calculated percent attributed risk (PAR) which, when multiplied by the number of SIDS deaths in the exposed cohort, yields the number of SIDS infants whose death is associated with maternal smoking  12 . In this analysis, 101 infant deaths due to SIDS bear an association with maternal smoking among the exposed cohort of 172 infants. Figure  1  demonstrates the increasing PAR associating maternal prenatal smoking and SIDS during the study period, suggesting a stronger link between SIDS and maternal smoking. The average rate for each 2-year period is plotted in the Figure as well. Time was a highly significant variable in the study and SIDS rates decreased markedly over the study time period. The remaining SIDS deaths show a greater relative association with maternal smoking in the years following the  Back to Sleep  campaign. In the final year of the analysis, 80% of the SIDS deaths in the smoke-exposed infant cohort are attributed to maternal smoking. Table 3 SIDS in smoke exposed and unexposed infants including attributed risk and deaths among smoke exposed infants by birth year, State of Colorado 1989–1998. Birth year SIDS deaths in: Total SIDS SIDS rate (SIDS/1000) in: Relative Risk PAR* Deaths Attributed to smoking smoke exp unexp smoke exposed unexp 1989 21 51 72 3.21 1.33 2.4 58 12 1990 24 53 77 2.96 1.35 2.2 54 13 1991 27 69 96 3.32 1.72 1.9 48 13 1992 21 59 80 2.93 1.41 2.1 52 11 1993 22 49 71 3.28 1.17 2.8 64 14 1994 10 34 44 1.65 0.79 5.6 52 5 1995 12 28 40 2.19 0.65 3.4 70 8 1996 9 36 45 1.61 0.82 2.0 49 4 1997 16 29 45 3.21 0.64 5.0 80 13 1998 10 18 28 1.80 0.37 4.9 79 8 TOTAL: 172 426 598 101 * Percent Attributed Risk in smoke-exposed cohort Figure 1 Percent attributed risk (PAR) between maternal prenatal smoking and sudden infant death, Colorado Birth Registry 1989–1998.
Results
Over the 10-year study period, 1573 infants died, 598 SIDS cases occurred (1.2/1000 live born infants), and 34 infants died due to a respiratory etiology. Table  1  describes characteristics of the exposed and unexposed infant cohorts. Smoking mothers were statistically more likely to be single, non-Hispanic, less educated, and to report alcohol use in pregnancy.Demographic characteristics of 488,918 births according to maternal smoking habits during pregnancy, Colorado Birth Registry, 1989 to 1998.Number (%)Reported maternal smoking (%)SexmalefemaleGestational age<37 weeksMarital status of mothermarriedsingleTime between births12 months or less>12 monthsMaternal Age17 years or less18 to 34 years35 years or moreMaternal Ethnicitycaucasianhispanicblackother/missingMaternal Educational level<high schoolhigh schoolsome collegecollegemore than collegemissingMaternal Alcohol usenone1 to 50 drinks/weekWe calculated adjusted odds ratios by analyzing smoking as a dichotomous exposure (mother smoked or did not smoke) and as a continuous variable (number of reported cigarettes per day during the pregnancy). Dichotomous outcomes of reported smoking during pregnancy yielded adjusted odds ratios of 1.9 (95% CI: 1.6 to 2.3) for death due to SIDS, 1.5 (95% CI: 1.3 to 1.7) for infant deaths from all causes, and 3.0 (95% CI: 1.4 to 6.3) for deaths due to respiratory etiologies (p < 0.01 for all outcomes). Table  2  shows results for the model for each of the outcomes. The final logistic regression model for each outcome was slightly different, but smoking remained in each as a significant factor. The interaction between ethnicity and cigarette use did not contribute significantly to the final model and thus was excluded.Adjusted odds ratios for SIDS, all infant deaths, and respiratory deaths with dichotomous cigarette use and other potential confounders*SIDSpAll deathspRespiratory deathspReported smokingGenderMarital statusPregnancy intervalGestational ageAny alcohol useEducationEthnicityYear of birth*Logistic regression modelling with corresponding p-values for each variableAnalyzing cigarette consumption as a continuous variable shows the associated odds  per cigarette  are 1.042 (95% CI: 1.030 to 1.054; p < 0.0001). In this model, consumption of 10 cigarettes per day is associated with a 51% increased odds of SIDS (95% risk limit 35% to 70%). The Hosmer-Lemeshow test statistic was non-significant (p > 0.1948) suggesting adequate model fit.per cigaretteTable  3  shows crude rates of SIDS in the exposed and unexposed cohorts of infants for the years 1989 to 1998. Included is a calculated percent attributed risk (PAR) which, when multiplied by the number of SIDS deaths in the exposed cohort, yields the number of SIDS infants whose death is associated with maternal smoking  12 . In this analysis, 101 infant deaths due to SIDS bear an association with maternal smoking among the exposed cohort of 172 infants. Figure  1  demonstrates the increasing PAR associating maternal prenatal smoking and SIDS during the study period, suggesting a stronger link between SIDS and maternal smoking. The average rate for each 2-year period is plotted in the Figure as well. Time was a highly significant variable in the study and SIDS rates decreased markedly over the study time period. The remaining SIDS deaths show a greater relative association with maternal smoking in the years following the  Back to Sleep  campaign. In the final year of the analysis, 80% of the SIDS deaths in the smoke-exposed infant cohort are attributed to maternal smoking.Back to SleepSIDS in smoke exposed and unexposed infants including attributed risk and deaths among smoke exposed infants by birth year, State of Colorado 1989–1998.* Percent Attributed Risk in smoke-exposed cohortDiscussion Smoking is deleterious and has negative effects on children born to mothers who smoke [ 12 - 16 ]. We confirm a two-fold increased risk of SIDS in infants born to smoking mothers. In addition, as one cause of SIDS (prone sleeping) was reduced through the  Back to Sleep  public health campaign in the United States, we noted an increasing attributed risk of SIDS with smoking. As a major etiology of SIDS, prone sleeping position, decreased over the study period due to the national educational campaign, the remaining SIDS deaths may now be due to the more isolated effects of tobacco exposure. Due to a decreased overall rate of SIDS, almost 80% of SIDS among smoke-exposed infants now bear a relationship to cigarette smoking. Taylor and Sanderson, using data prior to the  Back to Sleep  campaign in the United States, suggest that up to 30% of SIDS deaths may be attributed to maternal smoking [ 17 ]. We note an increasing percent attributed risk in our cohort of 489,000 infants after the roll out of the campaign. Using the attributed risk to calculate an absolute mortality among the exposed cohort, 101 of 172 infant SIDS cases over the 10-year study period are linked to maternal smoking, which is greater than half of the infant deaths due to SIDS in the smoke-exposed cohort. Our study cannot establish a causal role for maternal smoking in SIDS. Others have argued for a causal relationship based on prospective data, demonstrable dose-response relationships, and analysis using multiple potential confounders [ 18 ]. The causal path appears more likely on the basis of multiple studies that support such a link, consistent findings of a dose-response relationship in the literature, and a potential biological basis for the association between the exposure and the outcome [ 19 ]. In this study, removing one causative factor for SIDS, prone sleeping, may have increased the relative effect of another factor, maternal smoking, as an agent associated with SIDS. The published literature reports a 20% to 30% smoking rate among pregnant women [ 20 , 21 ]. Approximately 20% of pregnant smokers will deny smoking, but when tested with urine cotinine will be positive [ 22 ]. A recent report suggests that 21% of women in Colorado are smokers [ 23 ]. In our cohort, 15% of women reported some smoking during pregnancy, which may indicate a degree of under-reporting consistent with the published literature. While about one-fourth of women quit smoking during pregnancy, the recidivism rate is high and women are most likely to continue smoking into the postnatal period [ 24 - 26 ]. Furthermore, as most individuals who smoke begin before the age of 18 years [ 27 ], the results reported here provide yet another clarion call to eliminate smoking initiation and remove this preventable risk factor for infant death and SIDS. Expectant mothers, women desiring pregnancy, and health care providers who care for them need to be reminded about this strong association of infant death with the preventable risk factor of maternal smoking. For example, physicians can counsel women desiring or planning pregnancy that if they smoke, the child will have a markedly increased risk of SIDS due to the smoking. This study has several important limitations related to design and the nature of the data set used. Given the rich nature of the Colorado Birth Registry, we controlled for many potential confounding variables, but others may exist. This analysis likely represents an under-estimate of the actual associated risk with prenatal smoking, given that it relies on maternal report of a behavior widely known to be harmful. We suspect that self-report of maternal smoking underestimates the true rate of maternal smoking. Fetal and infant exposure to tobacco smoke occurs in manner ways, including prenatal maternal smoking, prenatal maternal second-hand smoke exposure, and postnatal smoke exposure by one or more care providers in the home. In this study we cannot distinguish among these exposure pathways, which may result in an erroneous under or over estimate of risk. The time period spanned by this study includes the rollout of the  Back to Sleep  campaign in the United States and our dataset did not assess whether parents positioned their infants prone or supine. We therefore could not control for this ecological association with SIDS. The very nature of retrospective data creates limitations in that we cannot carefully control the setting in which the data are collected, or the individual collecting the data. Missing data records are a third limitation, although this appears to have not been a major issue with this dataset.
Discussion
Smoking is deleterious and has negative effects on children born to mothers who smoke [ 12 - 16 ]. We confirm a two-fold increased risk of SIDS in infants born to smoking mothers. In addition, as one cause of SIDS (prone sleeping) was reduced through the  Back to Sleep  public health campaign in the United States, we noted an increasing attributed risk of SIDS with smoking. As a major etiology of SIDS, prone sleeping position, decreased over the study period due to the national educational campaign, the remaining SIDS deaths may now be due to the more isolated effects of tobacco exposure. Due to a decreased overall rate of SIDS, almost 80% of SIDS among smoke-exposed infants now bear a relationship to cigarette smoking.Back to SleepTaylor and Sanderson, using data prior to the  Back to Sleep  campaign in the United States, suggest that up to 30% of SIDS deaths may be attributed to maternal smoking [ 17 ]. We note an increasing percent attributed risk in our cohort of 489,000 infants after the roll out of the campaign. Using the attributed risk to calculate an absolute mortality among the exposed cohort, 101 of 172 infant SIDS cases over the 10-year study period are linked to maternal smoking, which is greater than half of the infant deaths due to SIDS in the smoke-exposed cohort.Back to SleepOur study cannot establish a causal role for maternal smoking in SIDS. Others have argued for a causal relationship based on prospective data, demonstrable dose-response relationships, and analysis using multiple potential confounders [ 18 ]. The causal path appears more likely on the basis of multiple studies that support such a link, consistent findings of a dose-response relationship in the literature, and a potential biological basis for the association between the exposure and the outcome [ 19 ]. In this study, removing one causative factor for SIDS, prone sleeping, may have increased the relative effect of another factor, maternal smoking, as an agent associated with SIDS.The published literature reports a 20% to 30% smoking rate among pregnant women [ 20 , 21 ]. Approximately 20% of pregnant smokers will deny smoking, but when tested with urine cotinine will be positive [ 22 ]. A recent report suggests that 21% of women in Colorado are smokers [ 23 ]. In our cohort, 15% of women reported some smoking during pregnancy, which may indicate a degree of under-reporting consistent with the published literature. While about one-fourth of women quit smoking during pregnancy, the recidivism rate is high and women are most likely to continue smoking into the postnatal period [ 24 - 26 ]. Furthermore, as most individuals who smoke begin before the age of 18 years [ 27 ], the results reported here provide yet another clarion call to eliminate smoking initiation and remove this preventable risk factor for infant death and SIDS. Expectant mothers, women desiring pregnancy, and health care providers who care for them need to be reminded about this strong association of infant death with the preventable risk factor of maternal smoking. For example, physicians can counsel women desiring or planning pregnancy that if they smoke, the child will have a markedly increased risk of SIDS due to the smoking.This study has several important limitations related to design and the nature of the data set used. Given the rich nature of the Colorado Birth Registry, we controlled for many potential confounding variables, but others may exist. This analysis likely represents an under-estimate of the actual associated risk with prenatal smoking, given that it relies on maternal report of a behavior widely known to be harmful. We suspect that self-report of maternal smoking underestimates the true rate of maternal smoking. Fetal and infant exposure to tobacco smoke occurs in manner ways, including prenatal maternal smoking, prenatal maternal second-hand smoke exposure, and postnatal smoke exposure by one or more care providers in the home. In this study we cannot distinguish among these exposure pathways, which may result in an erroneous under or over estimate of risk. The time period spanned by this study includes the rollout of the  Back to Sleep  campaign in the United States and our dataset did not assess whether parents positioned their infants prone or supine. We therefore could not control for this ecological association with SIDS. The very nature of retrospective data creates limitations in that we cannot carefully control the setting in which the data are collected, or the individual collecting the data. Missing data records are a third limitation, although this appears to have not been a major issue with this dataset.Back to SleepConclusions As prone infant sleeping has decreased, other causes of SIDS such as maternal smoking assume increased importance in the effort to protect infants from SIDS. Spanning the rollout of the  Back to Sleep  campaign in the United States we examined the increasing attributed risk associating smoking with SIDS. As SIDS rates declined, the attributed risk of SIDS with smoking has increased. In the final year of analysis, we demonstrated a link between 80% of the SIDS deaths and maternal smoking. A major, preventable exposure remains for infants in the United States and providers should redouble counseling efforts toward reducing this exposure.
Conclusions
As prone infant sleeping has decreased, other causes of SIDS such as maternal smoking assume increased importance in the effort to protect infants from SIDS. Spanning the rollout of the  Back to Sleep  campaign in the United States we examined the increasing attributed risk associating smoking with SIDS. As SIDS rates declined, the attributed risk of SIDS with smoking has increased. In the final year of analysis, we demonstrated a link between 80% of the SIDS deaths and maternal smoking. A major, preventable exposure remains for infants in the United States and providers should redouble counseling efforts toward reducing this exposure.Back to SleepCompeting interests The author(s) declare that they have no competing interests.
Competing interests
The author(s) declare that they have no competing interests.Authors' contributions MA participated in the study conception, background research, study design, statistical analysis, and drafting of the manuscript. DJ participated in the study conception, study design, and proofreading of the manuscript. HB participated in the study conception, study design, statistical analysis, and proofreading of the manuscript.
Authors' contributions
MA participated in the study conception, background research, study design, statistical analysis, and drafting of the manuscript. DJ participated in the study conception, study design, and proofreading of the manuscript. HB participated in the study conception, study design, statistical analysis, and proofreading of the manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here:


Drug industry insiders share their tips on using celebrities to market drugs and diseases

As the Hispanic world well knows, the word in Spanish for advertising is ‘propaganda’, its meaning derived literally from the propagation of the faith, the antithesis of science's Enlightenment ideals. The old word somehow seems perfect for describing the new world of drug promotion and its growing use of the famous face. Like the catholic cardinals of the 17th century, many of the feted celebrities of the 21st are now engaged in spreading the word. Now, as then, the religion promises miraculous breakthroughs, wonder cures, and sometimes even eternal life. The difference is that this time around, the stars are earning fat fees from the marketing departments of giant pharmaceutical companies. And if the latest revelations from industry insiders are anything to go by, their hefty investments in celebrity selling are well worth it.Celebrity Selling The epicentre of this phenomenon is of course the United States, where companies routinely hire celebrities to attract attention to the latest drugs and the diseases that go with them. Pfizer famously paid presidential hopeful Bob Dole to promote awareness of erectile dysfunction as sildenafil (Viagra) was hitting the market. Wyeth hired supermodel Lauren Hutton to hawk hormone replacement therapy and menopause. GSK contracted football star Ricky Williams to sell social anxiety disorder, helping make paroxetine (Paxil)—briefly—the world's top-selling antidepressant. Even the dead are raising awareness, with the estate of Errol Flynn now enlisted to help promote cardiovascular disease as a household name [ 1 ]. The celebrity, living or dead, becomes integral to a drug marketing strategy that includes paid advertising and aggressive public relations campaigns that can produce media appearances on the likes of  Oprah  and  The Today Show . According to celebrity brokers, the star's remuneration package, though always confidential, can range from $20,000 to $2 million.
 Celebrities often hide their conflicts of interest (Illustration: Margaret Shear) ‘A partnership between a celebrity and a brand has an intangible sort of magic’, writes a senior marketing executive at Amgen, in an extremely candid piece published recently in an industry trade magazine [ 2 ]. Amgen is the Californian biotech firm that hired handsome ‘West Wing’ star Rob Lowe to help market an anti-infection drug. Lowe was reportedly paid more than $1 million by Amgen, though there is speculation that part of the fee might flow to charity [ 3 ]. In her report, Amgen's Osnat Benshoshan shares some thoughtful tips with her peers among the pharmaceutical marketing fraternity: ‘use an A-list celebrity’; find a ‘news-hook’ that links the celebrity and your product; develop some simple messages; and make sure the celebrity delivers them at every appearance. Benshoshan then reveals why on-air talk-show appearances on ‘top-tier media venues’ like  The Rosie Show  can be better forums for celebrities than straight advertisements, which are governed by regulations. ‘The great advantage over advertising is that the airtime is practically free, and there is no fair balance to worry about’ she writes [ 2 ]. The downside with a media interview, she laments, is that compared to a scripted ad, ‘the situation is less controllable. It can be tricky for the celebrity to ensure that all product messages are delivered….’ Her other big tip for drug-makers is to rate your prospective celebrity with a ‘Q score’, a measure of their likeability and recognisability with the public. Apparently Rob Lowe's Q score was high with women over fifty, a key target of the Amgen campaign [ 3 ]. Another recent report from within the industry draws on public opinion survey data to guide drug company marketers on the selection and ‘effective use’ of celebrity spokespersons [ 4 ]. The survey was conducted by a Seattle firm called NexCura Inc., in partnership with the trade magazine that published the study. The major findings echo the insights of the Amgen executive about credibility, and underline the importance of your star being perceived as generally trustworthy, and specifically knowledgeable about the condition on which they are hired to speak. Perhaps not surprisingly, the survey found that people diagnosed as suffering chronic conditions were far more attentive to celebrity messages on health than the general public. The issue of credibility is important, the NexCura Inc. researchers point out, because ‘the credibility rating is used as a surrogate for “buying” behavior’—an intermediate measure of whether the star can persuade people to request the target drug from their doctor. The survey found that Bob Dole was still the most recognisable celebrity marketer with the United States public, but that the skater Dorothy Hamill—currently promoting Merck's arthritis medication rofecoxib (Vioxx)—took the lead in the credibility stakes. Significantly though, almost three-quarters of those surveyed were correctly able to identify Bob Dole with Pfizer's Viagra, despite the fact that the advertisements in which he appeared were ‘unbranded’ ads for erectile dysfunction. The researchers concluded by recommending that drug companies choose a celebrity with personal experience of the target condition; choose someone trustworthy—perhaps a newsreader or sports figure; and choose someone who will promote a single cause or brand rather than multiple ones. Ironically, the NexCura survey also found two-thirds of medical consumers agreed with the proposition that celebrities were ‘just doing it for the money and can't be trusted’.
Celebrity Selling
The epicentre of this phenomenon is of course the United States, where companies routinely hire celebrities to attract attention to the latest drugs and the diseases that go with them. Pfizer famously paid presidential hopeful Bob Dole to promote awareness of erectile dysfunction as sildenafil (Viagra) was hitting the market. Wyeth hired supermodel Lauren Hutton to hawk hormone replacement therapy and menopause. GSK contracted football star Ricky Williams to sell social anxiety disorder, helping make paroxetine (Paxil)—briefly—the world's top-selling antidepressant. Even the dead are raising awareness, with the estate of Errol Flynn now enlisted to help promote cardiovascular disease as a household name [ 1 ]. The celebrity, living or dead, becomes integral to a drug marketing strategy that includes paid advertising and aggressive public relations campaigns that can produce media appearances on the likes of  Oprah  and  The Today Show . According to celebrity brokers, the star's remuneration package, though always confidential, can range from $20,000 to $2 million.OprahThe Today Show‘A partnership between a celebrity and a brand has an intangible sort of magic’, writes a senior marketing executive at Amgen, in an extremely candid piece published recently in an industry trade magazine [ 2 ]. Amgen is the Californian biotech firm that hired handsome ‘West Wing’ star Rob Lowe to help market an anti-infection drug. Lowe was reportedly paid more than $1 million by Amgen, though there is speculation that part of the fee might flow to charity [ 3 ]. In her report, Amgen's Osnat Benshoshan shares some thoughtful tips with her peers among the pharmaceutical marketing fraternity: ‘use an A-list celebrity’; find a ‘news-hook’ that links the celebrity and your product; develop some simple messages; and make sure the celebrity delivers them at every appearance.Benshoshan then reveals why on-air talk-show appearances on ‘top-tier media venues’ like  The Rosie Show  can be better forums for celebrities than straight advertisements, which are governed by regulations. ‘The great advantage over advertising is that the airtime is practically free, and there is no fair balance to worry about’ she writes [ 2 ]. The downside with a media interview, she laments, is that compared to a scripted ad, ‘the situation is less controllable. It can be tricky for the celebrity to ensure that all product messages are delivered….’ Her other big tip for drug-makers is to rate your prospective celebrity with a ‘Q score’, a measure of their likeability and recognisability with the public. Apparently Rob Lowe's Q score was high with women over fifty, a key target of the Amgen campaign [ 3 ].The Rosie ShowAnother recent report from within the industry draws on public opinion survey data to guide drug company marketers on the selection and ‘effective use’ of celebrity spokespersons [ 4 ]. The survey was conducted by a Seattle firm called NexCura Inc., in partnership with the trade magazine that published the study. The major findings echo the insights of the Amgen executive about credibility, and underline the importance of your star being perceived as generally trustworthy, and specifically knowledgeable about the condition on which they are hired to speak. Perhaps not surprisingly, the survey found that people diagnosed as suffering chronic conditions were far more attentive to celebrity messages on health than the general public.The issue of credibility is important, the NexCura Inc. researchers point out, because ‘the credibility rating is used as a surrogate for “buying” behavior’—an intermediate measure of whether the star can persuade people to request the target drug from their doctor. The survey found that Bob Dole was still the most recognisable celebrity marketer with the United States public, but that the skater Dorothy Hamill—currently promoting Merck's arthritis medication rofecoxib (Vioxx)—took the lead in the credibility stakes. Significantly though, almost three-quarters of those surveyed were correctly able to identify Bob Dole with Pfizer's Viagra, despite the fact that the advertisements in which he appeared were ‘unbranded’ ads for erectile dysfunction. The researchers concluded by recommending that drug companies choose a celebrity with personal experience of the target condition; choose someone trustworthy—perhaps a newsreader or sports figure; and choose someone who will promote a single cause or brand rather than multiple ones.Ironically, the NexCura survey also found two-thirds of medical consumers agreed with the proposition that celebrities were ‘just doing it for the money and can't be trusted’.The Trouble with Celebrity Selling The first problem here is that the public is often not even informed whether a celebrity is receiving money from a drug company. In the case of TV star Rob Lowe, there was no mandated requirement for him to disclose his link with Amgen when appearing on media shows watched by millions. According to one industry insider familiar with the case, who did not want to be named, ‘it depended if he remembered to say it, and whether he was asked’. The media's failure to disclose relevant conflicts of interest when covering healthcare is well established [ 5 ]. When  Frasier  star Kelsey Grammer and his wife were promoting irritable bowel syndrome on top-rating TV shows, viewers thought the pair were speaking on behalf of an independent foundation. In fact the couple's fee had flowed from GSK, which was at that time preparing the market for alosetron (Lotronex), a controversial new drug that carried modest benefits and severe side effects, including possible death [ 6 ]. Equally as serious is the lack of any formal requirement for stars or media outlets to spell out drug side effects along with benefits when celebrities are pushing products or conditions. Lauren Hutton can be quoted, in magazine articles read by millions of readers, as saying, ‘My No. 1 secret is estrogen’ without any need for her, or the magazine, to list the dangers of the hormone replacement therapy made by her sponsor [ 7 ]. But perhaps most troubling is the way celebrities, with their star power, can help to fundamentally shift the public debate about major health problems. While Prince Charles's companion Camilla Parker Bowles takes no money from drug companies, she did choose to make an important public statement about the bone condition osteoporosis at an international conference funded by Lilly, a company promoting a medication for the condition [ 8 ]. Camilla's call for early intervention and greater use of expensive tests and technologies for the primary prevention of osteoporosis drew on materials sponsored by the pharmaceutical industry, and was synchronised with simplistic industry marketing messages. Camilla's high-profile intervention at a drug company sponsored forum, albeit unwittingly, helps keep the focus on biochemical causes of, and biochemical solutions to, the much wider public health problem of fractures. Moreover these simple marketing messages undermine the complexity of the cost-effectiveness arguments that are central to any rational debate about the equitable distribution of health care resources. Other high-profile figures attending the same conference eagerly accepted Lilly money, and one, former Texas Governor Ann Richards, blatantly promoted Lilly's drug during an interview on CNN's Larry King Show just days later [ 8 ].
The Trouble with Celebrity Selling
The first problem here is that the public is often not even informed whether a celebrity is receiving money from a drug company. In the case of TV star Rob Lowe, there was no mandated requirement for him to disclose his link with Amgen when appearing on media shows watched by millions. According to one industry insider familiar with the case, who did not want to be named, ‘it depended if he remembered to say it, and whether he was asked’. The media's failure to disclose relevant conflicts of interest when covering healthcare is well established [ 5 ]. When  Frasier  star Kelsey Grammer and his wife were promoting irritable bowel syndrome on top-rating TV shows, viewers thought the pair were speaking on behalf of an independent foundation. In fact the couple's fee had flowed from GSK, which was at that time preparing the market for alosetron (Lotronex), a controversial new drug that carried modest benefits and severe side effects, including possible death [ 6 ].FrasierEqually as serious is the lack of any formal requirement for stars or media outlets to spell out drug side effects along with benefits when celebrities are pushing products or conditions. Lauren Hutton can be quoted, in magazine articles read by millions of readers, as saying, ‘My No. 1 secret is estrogen’ without any need for her, or the magazine, to list the dangers of the hormone replacement therapy made by her sponsor [ 7 ]. But perhaps most troubling is the way celebrities, with their star power, can help to fundamentally shift the public debate about major health problems.While Prince Charles's companion Camilla Parker Bowles takes no money from drug companies, she did choose to make an important public statement about the bone condition osteoporosis at an international conference funded by Lilly, a company promoting a medication for the condition [ 8 ]. Camilla's call for early intervention and greater use of expensive tests and technologies for the primary prevention of osteoporosis drew on materials sponsored by the pharmaceutical industry, and was synchronised with simplistic industry marketing messages. Camilla's high-profile intervention at a drug company sponsored forum, albeit unwittingly, helps keep the focus on biochemical causes of, and biochemical solutions to, the much wider public health problem of fractures. Moreover these simple marketing messages undermine the complexity of the cost-effectiveness arguments that are central to any rational debate about the equitable distribution of health care resources. Other high-profile figures attending the same conference eagerly accepted Lilly money, and one, former Texas Governor Ann Richards, blatantly promoted Lilly's drug during an interview on CNN's Larry King Show just days later [ 8 ].The Future of Celebrity Selling With pharmaceutical marketing, it is clear that nothing short of a Vatican II-style reform is required, though there are already encouraging signs of change. Scientific journals are slowly disentangling themselves from unhealthy industry influence over what they publish, and public access to clinical trial data is daily a closer reality [ 9 ]. However, a less distorted scientific record about healthcare products is meaningless without regulations on how important science is communicated to the public. Celebrities paid by drug companies to promote drugs, or ‘raise awareness’ about disease, should be subject to the same rules as direct-to-consumer advertising, which would mean prohibition in many nations and much more fulsome disclosure in the United States than is currently the case. At the very least, public disclosure of a product's risks and benefits, and the magnitude of the celebrity's fee, should be mandatory and routine. Let's see what that does to their Q rating.
The Future of Celebrity Selling
With pharmaceutical marketing, it is clear that nothing short of a Vatican II-style reform is required, though there are already encouraging signs of change. Scientific journals are slowly disentangling themselves from unhealthy industry influence over what they publish, and public access to clinical trial data is daily a closer reality [ 9 ]. However, a less distorted scientific record about healthcare products is meaningless without regulations on how important science is communicated to the public. Celebrities paid by drug companies to promote drugs, or ‘raise awareness’ about disease, should be subject to the same rules as direct-to-consumer advertising, which would mean prohibition in many nations and much more fulsome disclosure in the United States than is currently the case. At the very least, public disclosure of a product's risks and benefits, and the magnitude of the celebrity's fee, should be mandatory and routine. Let's see what that does to their Q rating.