- Email: [email protected]
Relationship of large and small airway response with inhaled corticosteroid to asthma control
140
Letters / Ann Allergy Asthma Immunol 111 (2013) 138e148
Table 1 Patch testing to betalactam antibiotics in our patient Drug
Benzylpenicillin Cephalothin Meropenem Ertapenem Clindamycin
Solution/vehicle Water 10% w/v
Water 30% w/v
Petrolatum 10% w/v
Petrolatum 30% w/v
þ þþ þþ þþ -
þþ þþ þþ þþ -
þ þ þþ þþ -
þþ þþ þþ þþ -
-, negative patch test; þ, weakly positive patch test characterized by erythema and mild nonfollicular pustular reaction; þþ, strongly positive patch test characterized by a coalescing nonfollicular pustular reaction.
administered ertapenem, and after 2 days he developed fever and a generalized nonfollicular pustular rash, which was especially prominent over the axillary and inguinal folds. Investigations revealed a marked neutrophilia of 28 109 cells/L on the day of the onset of the rash in contrast to a normal neutrophil count of 7.1 109 cells/L on the previous day. Bacterial cultures of blood, urine, and a swab of a pustule were negative. His chest x-ray was normal. His c-reactive protein, liver function, and renal function test results were normal. A diagnosis of AGEP was made and supported by a skin biopsy, which revealed intraepidermal and subcorneal spongiform pustules with papillary edema. Ertapenem was subsequently ceased, and he was placed on linezolid, which resulted in resolution of his cellulitis. His AGEP resolved without the need for corticosteroids over the ensuing 2 weeks. After the resolution of his rash he was found to be patch test positive at 48 hours to penicillin, cephalothin, meropenem, and ertapenem. His patch test to clindamycin was negative after 1 week of observation (Table 1). This case demonstrates AGEP to multiple beta-lactam antibiotics and is likely to represent a type IVd hypersensitivity to the common beta-lactam ring. The patient was able to recollect that his
hypersensitivity rashes to penicillin and cephalexin as a teenager exhibited the same characteristics of fever and pustulosis. The case as reported by Mysore and Ghuloom4 depicts recurrent episodes of AGEP in a patient exposed sequentially to a penicillin, cephalosporin, and carbapenem over an 8-week period. In the absence of patch testing, it is possible that the second or third episode of AGEP was a flareup reaction occurring in the setting of a highly activated T cell pool rather than a result of cross-sensitivity.6 Further studies need to be conducted to determine the rates of cross-reactivity of penicillin, cephalosporins, and carbapenems in AGEP and the pathogenic mechanisms including the allergenic determinants and predisposing host factors such as HLA status. This may ultimately help clinicians stratify the risk of developing this severe cutaneous adverse reaction in individual patients. Suran L. Fernando, PhD, FRACP, FRCPA Department of Clinical Immunology and Allergy Royal North Shore Hospital Sydney Medical SchooldNorthern Sydney University Sydney, Australia [email protected] References [1] Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology. 2005; 209:123e129. [2] Brandenburg VM, Kurts C, Eitner F, Hamilton-Williams E, Heintz B. Acute reversible renal failure in acute generalized exanthematous pustulosis. Nephrol Dial Transplant. 2002;17:1857e1858. [3] Fernando SL. Acute generalised exanthemtous pustulosis. Australas J Dermatol. 2012;53:87e92. [4] Mysore V, Ghuloom A. A case of recurrent acute generalized exanthematous pustulosis due to beta-lactam antibiotics: a case report. J Dermatol Treat. 2003; 14:54e56. [5] Sawada Y, Sugita K, Fukamachi S, Bito T, Nakamura M, Tokura Y. Doripeneminduced intertriginous drug eruption as a mild form of AGEP. J Eur Acad Dermatol Venereol. 2009;23:974e976. [6] Hausmann O, Schnyder B, Pichler WJ. Etiology and pathogenesis of adverse drug reactions. Chem Immunol Allergy. 2012;97:32e46.
Relationship of large and small airway response with inhaled corticosteroid to asthma control Small airways have traditionally been difficult to assess with conventional spirometry. Flow between 25% and 75% of vital capacity (FEF25-75) is often used to assess small airways response, but FEF25-75 is an effort-dependent test and therefore susceptible to marked variability. The various methods to assess small airway function have been detailed elsewhere.1 More recently, impulse oscillometry (IOS) has been used to assess small airway function.2 IOS is an effort-independent test performed during normal quiet tidal breathing and is able to discriminate between changes in central and peripheral airways. The research question was to compare large and small airway outcomes with low-dose inhaled corticosteroid (ICS) and to investigate their relationships to asthma control using the Asthma Control Questionnaire (ACQ-5), using post-hoc analysis of a previous study described in detail elsewhere.3 Twenty-one patients with mild-to-moderate persistent asthma completed the study per protocol. At baseline, patients were taking
Disclosures: Professor Lipworth has received unrestricted educational grants from Teva Pharmaceuticals USA and Chiesi Ltd; is on the Speaker Bureau for Teva and Advisory Board for Chiesi. Funding Sources: This study was funded by a departmental grant from the University of Dundee as part of an unrestricted research grant from Teva Pharmaceuticals USA.
a mean beclomethasone dipropionate equivalent dose of 441 mg/ day with mean forced expiratory volume in 1 second (FEV1) 88.5%, FEF25-75 53%, resistance at 5 Hz (R5) 118%, ACQ 1.15, age 36.7 years. After a 2-week ICS-free washout period, both large (FEV1, R5) and small airway (FEF25-75, R5eR20) outcomes significantly correlated with ACQ-5 (Fig 1). After 2 weeks of treatment with inhaled fluticasone propionate 50 mg one puff bid (FP100), mean ACQ-5 scores improved significantly from a baseline of 1.15 (95% confidence interval [CI]: 0.77e1.53) to 0.43 (95% CI: 0.21e0.66) (P ¼ .001). The change in ACQ-5 correlated with the change in both large and small airway outcomes (Fig 1). When participants were categorized according to those who had an ACQ-5 change greater than the minimal important difference of 0.5 (n ¼ 11) and less than 0.5 (n ¼ 10), FEV1 improved in both groups (P ¼ .002 and P ¼ .04, respectively), R5 (P ¼ .03) and FEF25-75 (P < .0001) improved in the group with an ACQ change of greater than 0.5, but R5-R20 did not improve in either group. The results of the current study showed that both large (FEV1, R5) and small airway (FEF25-75, R5-R20) pulmonary function outcomes significantly correlated with ACQ at baseline and after 2 weeks of treatment with low-dose ICS. Pointedly, our patients had received no inhaled corticosteroid for 2 weeks before treatment
Letters / Ann Allergy Asthma Immunol 111 (2013) 138e148
141
Figure 1. Relationship between pulmonary function and ACQ-5 at baseline. A, FEV1 (% predicted); B, FEF25-75 (% predicted); C, R5 (% predicted); D, R5-R20 (kPa$s$L1). Values for ACQ <0.75 indicate well-controlled asthma; >1.0, not well controlled asthma; >1.5, inadequately controlled asthma. D (post-FP100 e baseline) in pulmonary function versus D ACQ. E, DFEV1 (% predicted); F, DFEF25-75 (%predicted); G, D R5 (% predicted); H, DR5-R20 (kPa$s$/L1). A change in AQ of >0.5 represents the minimal important difference.
with low-dose fluticasone propionate, to maximize the potential response. In addition, the use of second-line controller medications such as long-acting beta agonist or leukotriene receptor antagonists, which may confound the study outcomes, were not permitted during the study. As far as we are aware, there are no randomized controlled studies examining spirometry and IOS response with low-dose ICS in steroid-naive individuals. A recent study by Farah et al4 examined a broad range of physiological outcomes before and after ICS dose adjustment to determine predictors of asthma control (as ACQ-5), but the participants were not all steroid naïve, and long-acting beta agonist use was not prohibited.4
In spite of the short duration of ICS treatment, there were significant improvements in asthma control from baseline. After only 2 weeks of low-dose ICS treatment, the mean ACQ-5 scores improved to below the 0.75 level, which indicates well-controlled asthma starting from a baseline value of greater than 1, indicating not-well-controlled asthma.5 Pointedly, the upper 95% CI value (ie, 0.66) was less than 0.75, showing uniformity of response to lowdose ICS. Furthermore the mean change in ACQ-5 also exceeded the minimal important difference of 0.5.6 We acknowledge that with more prolonged treatment the change in ACQ may have been greater than that observed in the current study.
142
Letters / Ann Allergy Asthma Immunol 111 (2013) 138e148
In our study, FEV1, R5, FEF25-75, and R5-R20 all correlated with ACQ-5 at baseline. This would be in keeping with the study by Takeda et al,5 who measured spirometry and IOS in 65 patients with asthma and assessed associations with health status, dyspnea, and asthma control.7 The participants in their study, however, were not stepped off their usual ICS, and response to ICS treatment per se was not assessed. The ICS we used was a coarse particle suspensionebased hydrofluoroalkane formulation, which is preferentially deposited in the larger airways. Extra-fine particle ICS formulations with a mass median aerodynamic diameter less than 2 mm would be more likely to reach the small airways.1 Some evidence suggests that R5-R20 may better reflect small airway function than FEF25-75. Shi et al,8,9 in 2 recent studies have shown small airway parameters measured by IOS to be superior to spirometry in detecting poor asthma control as well as predicting loss of control in children.8,9 In another recent study in children with a normal FEV1, a low FEF25-75 was associated with increased asthma severity, systemic steroid use, and asthma exacerbations.10 The participants in this study were not selected based on pulmonary function. Most participants had a near ‘normal’ predicted FEV1 with a mean value of 88.5%. Interestingly, however, we were still able to demonstrate a significant correlation between the change in pulmonary function and the change in ACQ-5 from baseline with ICS. This observation would suggest that we should not dismiss the possibility of further improvements in pulmonary function with ICS, even when patients have near ‘normal’ predicted FEV1. In conclusion, this post hoc analysis shows that both large and small airways response to low-dose ICS correlated with asthma control using either spirometry or IOS. To further investigate the potential role of IOS, we advocate performing a randomized controlled trial using more prolonged treatment with an extra-fineparticle ICS solution formulation in patients with abnormal small airways function, to assess relationships with asthma control.
Arvind Manoharan, MBChB William J. Anderson, MBChB Brian J. Lipworth, MD Asthma and Allergy Research Group Division of Cardiovascular and Diabetes Medicine Medical Research Institute University of Dundee Ninewells Hospital and Medical School Dundee, Scotland, United Kingdom [email protected] References [1] Lipworth BJ. Targeting the small airways asthma phenotype: if we can reach it, should we treat it? Ann Allergy Asthma Immunol. 2013;110:233e239. [2] Williamson PA, Clearie K, Menzies D, Vaidyanathan S, Lipworth BJ. Assessment of small-airways disease using alveolar nitric oxide and impulse oscillometry in asthma and COPD. Lung. 2011;189:121e129. [3] Anderson WJ, Short PM, Williamson PA, Lipworth BJ. Inhaled corticosteroid dose response using domiciliary exhaled nitric oxide in persistent asthma: the FENOtype trial. Chest. 2012;142:1553e1561. [4] Farah CS, King GG, Brown NJ, Peters MJ, Berend N, Salome CM. Ventilation heterogeneity predicts asthma control in adults following inhaled corticosteroid dose titration. J Allergy Clin Immunol. 2012;130:61e68. [5] Takeda T, Oga T, Niimi A, et al. Relationship between small airway function and health status, dyspnea and disease control in asthma. Respiration. 2010; 80:120e126. [6] Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99:553e558. [7] Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med. 2006;100:616e621. [8] Shi Y, Aledia AS, Galant SP, George SC. Peripheral airway impairment measured by oscillometry predicts loss of asthma control in children. J Allergy Clin Immunol. 2013;131:718e723. [9] Shi Y, Aledia AS, Tatavoosian AV, Vijayalakshmi S, Galant SP, George SC. Relating small airways to asthma control by using impulse oscillometry in children. J Allergy Clin Immunol. 2012;129:671e678. [10] Rao DR, Gaffin JM, Baxi SN, Sheehan WJ, Hoffman EB, Phipatanakul W. The utility of forced expiratory flow between 25% and 75% of vital capacity in predicting childhood asthma morbidity and severity. J Asthma. 2012;49:586e592.
Congenital nephrotic syndrome and agammaglobulinemia: A therapeutic dilemma The primary immunodeficiency practice parameters outline use of gamma globulin as treatment for diseases of hypo- and agammaglobulinemia. There is no consensus, however, on use of immunoglobulin replacement in secondary immunodeficiencies such as protein-losing disease states. Congenital nephrotic syndrome is an exceedingly rare disorder lacking data on comorbid conditions such as agammaglobulinemia, although infection risk is known to be high as serious bacterial infection was demonstrated in 85% of a 41-patient cohort.1 Harris examined the use of intravenous immunoglobulin (IVIG) in a congenital nephrotic patient and showed that, within 30 hours, 55% could be found in the urine.2 A review evaluating the use of IVIG in pediatric nephrotic syndrome illustrated a significant benefit on preventing infection; however, the quality and sample sizes of the reviewed studies were called into question.3 IVIG treatments have even been shown to resolve proteinuria and improve kidney function in 1 small cohort of patients with congenital nephrotic syndrome secondary to diffuse mesangial sclerosis.4 In adult-onset nephrotic syndrome, IVIG has been shown to mitigate infections.5 Disclosures: Authors have nothing to disclose. Disclaimer: The views expressed in this letter are those of the authors and do not reflect the official policy of the Department of Army, Navy, Department of Defense, or U.S. government.
Intravenous immunoglobulin use has been evaluated in other protein-losing states. Studies have reported that IVIG can decrease infections, resolve edema, and result in better overall clinical status in patients with protein-losing enteropathy.6,7 Despite some of these successful case reports, most reviews do not support the use of IVIG in nephrotic syndrome given the expected quick urinary losses.8e10 No studies, however, evaluate the use of subcutaneous immunoglobulin infusions in this disease process. We report a case of congenital nephrotic syndrome with agammaglobulinemia and unsuccessful treatment with subcutaneous immunoglobulin infusions. A 1-month-old African American boy presented with increased work of breathing and low oxygen saturations, as well as periorbital edema. Evaluation was notable for a right-sided pleural effusion, very low serum protein (<2.8 g/dL) and albumin (1.6 g/dL), and large proteinuria. The patient was diagnosed with congenital nephrotic syndrome, with positive genetic analysis for a mutation in NPHS1 (nephrin gene), which is also known as the Finnish-type congenital nephrotic syndrome. During the course of his admission, the patient’s immunoglobulin levels were IgG < 70 mg/dL, IgA < 15 mg/dL, and IgM 24 mg/dL. Absolute lymphocyte count was in the low normal range for age at 3,869 cells/mm3. Flow cytometry showed a normal CD19þ cell count of 1,061 cell/mL and a low CD3þ cell count of 1,832 cells/mL. The patient was placed on antibiotic prophylaxis, but given
Letters / Ann Allergy Asthma Immunol 111 (2013) 138e148
Table 1 Patch testing to betalactam antibiotics in our patient Drug
Benzylpenicillin Cephalothin Meropenem Ertapenem Clindamycin
Solution/vehicle Water 10% w/v
Water 30% w/v
Petrolatum 10% w/v
Petrolatum 30% w/v
þ þþ þþ þþ -
þþ þþ þþ þþ -
þ þ þþ þþ -
þþ þþ þþ þþ -
-, negative patch test; þ, weakly positive patch test characterized by erythema and mild nonfollicular pustular reaction; þþ, strongly positive patch test characterized by a coalescing nonfollicular pustular reaction.
administered ertapenem, and after 2 days he developed fever and a generalized nonfollicular pustular rash, which was especially prominent over the axillary and inguinal folds. Investigations revealed a marked neutrophilia of 28 109 cells/L on the day of the onset of the rash in contrast to a normal neutrophil count of 7.1 109 cells/L on the previous day. Bacterial cultures of blood, urine, and a swab of a pustule were negative. His chest x-ray was normal. His c-reactive protein, liver function, and renal function test results were normal. A diagnosis of AGEP was made and supported by a skin biopsy, which revealed intraepidermal and subcorneal spongiform pustules with papillary edema. Ertapenem was subsequently ceased, and he was placed on linezolid, which resulted in resolution of his cellulitis. His AGEP resolved without the need for corticosteroids over the ensuing 2 weeks. After the resolution of his rash he was found to be patch test positive at 48 hours to penicillin, cephalothin, meropenem, and ertapenem. His patch test to clindamycin was negative after 1 week of observation (Table 1). This case demonstrates AGEP to multiple beta-lactam antibiotics and is likely to represent a type IVd hypersensitivity to the common beta-lactam ring. The patient was able to recollect that his
hypersensitivity rashes to penicillin and cephalexin as a teenager exhibited the same characteristics of fever and pustulosis. The case as reported by Mysore and Ghuloom4 depicts recurrent episodes of AGEP in a patient exposed sequentially to a penicillin, cephalosporin, and carbapenem over an 8-week period. In the absence of patch testing, it is possible that the second or third episode of AGEP was a flareup reaction occurring in the setting of a highly activated T cell pool rather than a result of cross-sensitivity.6 Further studies need to be conducted to determine the rates of cross-reactivity of penicillin, cephalosporins, and carbapenems in AGEP and the pathogenic mechanisms including the allergenic determinants and predisposing host factors such as HLA status. This may ultimately help clinicians stratify the risk of developing this severe cutaneous adverse reaction in individual patients. Suran L. Fernando, PhD, FRACP, FRCPA Department of Clinical Immunology and Allergy Royal North Shore Hospital Sydney Medical SchooldNorthern Sydney University Sydney, Australia [email protected] References [1] Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology. 2005; 209:123e129. [2] Brandenburg VM, Kurts C, Eitner F, Hamilton-Williams E, Heintz B. Acute reversible renal failure in acute generalized exanthematous pustulosis. Nephrol Dial Transplant. 2002;17:1857e1858. [3] Fernando SL. Acute generalised exanthemtous pustulosis. Australas J Dermatol. 2012;53:87e92. [4] Mysore V, Ghuloom A. A case of recurrent acute generalized exanthematous pustulosis due to beta-lactam antibiotics: a case report. J Dermatol Treat. 2003; 14:54e56. [5] Sawada Y, Sugita K, Fukamachi S, Bito T, Nakamura M, Tokura Y. Doripeneminduced intertriginous drug eruption as a mild form of AGEP. J Eur Acad Dermatol Venereol. 2009;23:974e976. [6] Hausmann O, Schnyder B, Pichler WJ. Etiology and pathogenesis of adverse drug reactions. Chem Immunol Allergy. 2012;97:32e46.
Relationship of large and small airway response with inhaled corticosteroid to asthma control Small airways have traditionally been difficult to assess with conventional spirometry. Flow between 25% and 75% of vital capacity (FEF25-75) is often used to assess small airways response, but FEF25-75 is an effort-dependent test and therefore susceptible to marked variability. The various methods to assess small airway function have been detailed elsewhere.1 More recently, impulse oscillometry (IOS) has been used to assess small airway function.2 IOS is an effort-independent test performed during normal quiet tidal breathing and is able to discriminate between changes in central and peripheral airways. The research question was to compare large and small airway outcomes with low-dose inhaled corticosteroid (ICS) and to investigate their relationships to asthma control using the Asthma Control Questionnaire (ACQ-5), using post-hoc analysis of a previous study described in detail elsewhere.3 Twenty-one patients with mild-to-moderate persistent asthma completed the study per protocol. At baseline, patients were taking
Disclosures: Professor Lipworth has received unrestricted educational grants from Teva Pharmaceuticals USA and Chiesi Ltd; is on the Speaker Bureau for Teva and Advisory Board for Chiesi. Funding Sources: This study was funded by a departmental grant from the University of Dundee as part of an unrestricted research grant from Teva Pharmaceuticals USA.
a mean beclomethasone dipropionate equivalent dose of 441 mg/ day with mean forced expiratory volume in 1 second (FEV1) 88.5%, FEF25-75 53%, resistance at 5 Hz (R5) 118%, ACQ 1.15, age 36.7 years. After a 2-week ICS-free washout period, both large (FEV1, R5) and small airway (FEF25-75, R5eR20) outcomes significantly correlated with ACQ-5 (Fig 1). After 2 weeks of treatment with inhaled fluticasone propionate 50 mg one puff bid (FP100), mean ACQ-5 scores improved significantly from a baseline of 1.15 (95% confidence interval [CI]: 0.77e1.53) to 0.43 (95% CI: 0.21e0.66) (P ¼ .001). The change in ACQ-5 correlated with the change in both large and small airway outcomes (Fig 1). When participants were categorized according to those who had an ACQ-5 change greater than the minimal important difference of 0.5 (n ¼ 11) and less than 0.5 (n ¼ 10), FEV1 improved in both groups (P ¼ .002 and P ¼ .04, respectively), R5 (P ¼ .03) and FEF25-75 (P < .0001) improved in the group with an ACQ change of greater than 0.5, but R5-R20 did not improve in either group. The results of the current study showed that both large (FEV1, R5) and small airway (FEF25-75, R5-R20) pulmonary function outcomes significantly correlated with ACQ at baseline and after 2 weeks of treatment with low-dose ICS. Pointedly, our patients had received no inhaled corticosteroid for 2 weeks before treatment
Letters / Ann Allergy Asthma Immunol 111 (2013) 138e148
141
Figure 1. Relationship between pulmonary function and ACQ-5 at baseline. A, FEV1 (% predicted); B, FEF25-75 (% predicted); C, R5 (% predicted); D, R5-R20 (kPa$s$L1). Values for ACQ <0.75 indicate well-controlled asthma; >1.0, not well controlled asthma; >1.5, inadequately controlled asthma. D (post-FP100 e baseline) in pulmonary function versus D ACQ. E, DFEV1 (% predicted); F, DFEF25-75 (%predicted); G, D R5 (% predicted); H, DR5-R20 (kPa$s$/L1). A change in AQ of >0.5 represents the minimal important difference.
with low-dose fluticasone propionate, to maximize the potential response. In addition, the use of second-line controller medications such as long-acting beta agonist or leukotriene receptor antagonists, which may confound the study outcomes, were not permitted during the study. As far as we are aware, there are no randomized controlled studies examining spirometry and IOS response with low-dose ICS in steroid-naive individuals. A recent study by Farah et al4 examined a broad range of physiological outcomes before and after ICS dose adjustment to determine predictors of asthma control (as ACQ-5), but the participants were not all steroid naïve, and long-acting beta agonist use was not prohibited.4
In spite of the short duration of ICS treatment, there were significant improvements in asthma control from baseline. After only 2 weeks of low-dose ICS treatment, the mean ACQ-5 scores improved to below the 0.75 level, which indicates well-controlled asthma starting from a baseline value of greater than 1, indicating not-well-controlled asthma.5 Pointedly, the upper 95% CI value (ie, 0.66) was less than 0.75, showing uniformity of response to lowdose ICS. Furthermore the mean change in ACQ-5 also exceeded the minimal important difference of 0.5.6 We acknowledge that with more prolonged treatment the change in ACQ may have been greater than that observed in the current study.
142
Letters / Ann Allergy Asthma Immunol 111 (2013) 138e148
In our study, FEV1, R5, FEF25-75, and R5-R20 all correlated with ACQ-5 at baseline. This would be in keeping with the study by Takeda et al,5 who measured spirometry and IOS in 65 patients with asthma and assessed associations with health status, dyspnea, and asthma control.7 The participants in their study, however, were not stepped off their usual ICS, and response to ICS treatment per se was not assessed. The ICS we used was a coarse particle suspensionebased hydrofluoroalkane formulation, which is preferentially deposited in the larger airways. Extra-fine particle ICS formulations with a mass median aerodynamic diameter less than 2 mm would be more likely to reach the small airways.1 Some evidence suggests that R5-R20 may better reflect small airway function than FEF25-75. Shi et al,8,9 in 2 recent studies have shown small airway parameters measured by IOS to be superior to spirometry in detecting poor asthma control as well as predicting loss of control in children.8,9 In another recent study in children with a normal FEV1, a low FEF25-75 was associated with increased asthma severity, systemic steroid use, and asthma exacerbations.10 The participants in this study were not selected based on pulmonary function. Most participants had a near ‘normal’ predicted FEV1 with a mean value of 88.5%. Interestingly, however, we were still able to demonstrate a significant correlation between the change in pulmonary function and the change in ACQ-5 from baseline with ICS. This observation would suggest that we should not dismiss the possibility of further improvements in pulmonary function with ICS, even when patients have near ‘normal’ predicted FEV1. In conclusion, this post hoc analysis shows that both large and small airways response to low-dose ICS correlated with asthma control using either spirometry or IOS. To further investigate the potential role of IOS, we advocate performing a randomized controlled trial using more prolonged treatment with an extra-fineparticle ICS solution formulation in patients with abnormal small airways function, to assess relationships with asthma control.
Arvind Manoharan, MBChB William J. Anderson, MBChB Brian J. Lipworth, MD Asthma and Allergy Research Group Division of Cardiovascular and Diabetes Medicine Medical Research Institute University of Dundee Ninewells Hospital and Medical School Dundee, Scotland, United Kingdom [email protected] References [1] Lipworth BJ. Targeting the small airways asthma phenotype: if we can reach it, should we treat it? Ann Allergy Asthma Immunol. 2013;110:233e239. [2] Williamson PA, Clearie K, Menzies D, Vaidyanathan S, Lipworth BJ. Assessment of small-airways disease using alveolar nitric oxide and impulse oscillometry in asthma and COPD. Lung. 2011;189:121e129. [3] Anderson WJ, Short PM, Williamson PA, Lipworth BJ. Inhaled corticosteroid dose response using domiciliary exhaled nitric oxide in persistent asthma: the FENOtype trial. Chest. 2012;142:1553e1561. [4] Farah CS, King GG, Brown NJ, Peters MJ, Berend N, Salome CM. Ventilation heterogeneity predicts asthma control in adults following inhaled corticosteroid dose titration. J Allergy Clin Immunol. 2012;130:61e68. [5] Takeda T, Oga T, Niimi A, et al. Relationship between small airway function and health status, dyspnea and disease control in asthma. Respiration. 2010; 80:120e126. [6] Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99:553e558. [7] Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med. 2006;100:616e621. [8] Shi Y, Aledia AS, Galant SP, George SC. Peripheral airway impairment measured by oscillometry predicts loss of asthma control in children. J Allergy Clin Immunol. 2013;131:718e723. [9] Shi Y, Aledia AS, Tatavoosian AV, Vijayalakshmi S, Galant SP, George SC. Relating small airways to asthma control by using impulse oscillometry in children. J Allergy Clin Immunol. 2012;129:671e678. [10] Rao DR, Gaffin JM, Baxi SN, Sheehan WJ, Hoffman EB, Phipatanakul W. The utility of forced expiratory flow between 25% and 75% of vital capacity in predicting childhood asthma morbidity and severity. J Asthma. 2012;49:586e592.
Congenital nephrotic syndrome and agammaglobulinemia: A therapeutic dilemma The primary immunodeficiency practice parameters outline use of gamma globulin as treatment for diseases of hypo- and agammaglobulinemia. There is no consensus, however, on use of immunoglobulin replacement in secondary immunodeficiencies such as protein-losing disease states. Congenital nephrotic syndrome is an exceedingly rare disorder lacking data on comorbid conditions such as agammaglobulinemia, although infection risk is known to be high as serious bacterial infection was demonstrated in 85% of a 41-patient cohort.1 Harris examined the use of intravenous immunoglobulin (IVIG) in a congenital nephrotic patient and showed that, within 30 hours, 55% could be found in the urine.2 A review evaluating the use of IVIG in pediatric nephrotic syndrome illustrated a significant benefit on preventing infection; however, the quality and sample sizes of the reviewed studies were called into question.3 IVIG treatments have even been shown to resolve proteinuria and improve kidney function in 1 small cohort of patients with congenital nephrotic syndrome secondary to diffuse mesangial sclerosis.4 In adult-onset nephrotic syndrome, IVIG has been shown to mitigate infections.5 Disclosures: Authors have nothing to disclose. Disclaimer: The views expressed in this letter are those of the authors and do not reflect the official policy of the Department of Army, Navy, Department of Defense, or U.S. government.
Intravenous immunoglobulin use has been evaluated in other protein-losing states. Studies have reported that IVIG can decrease infections, resolve edema, and result in better overall clinical status in patients with protein-losing enteropathy.6,7 Despite some of these successful case reports, most reviews do not support the use of IVIG in nephrotic syndrome given the expected quick urinary losses.8e10 No studies, however, evaluate the use of subcutaneous immunoglobulin infusions in this disease process. We report a case of congenital nephrotic syndrome with agammaglobulinemia and unsuccessful treatment with subcutaneous immunoglobulin infusions. A 1-month-old African American boy presented with increased work of breathing and low oxygen saturations, as well as periorbital edema. Evaluation was notable for a right-sided pleural effusion, very low serum protein (<2.8 g/dL) and albumin (1.6 g/dL), and large proteinuria. The patient was diagnosed with congenital nephrotic syndrome, with positive genetic analysis for a mutation in NPHS1 (nephrin gene), which is also known as the Finnish-type congenital nephrotic syndrome. During the course of his admission, the patient’s immunoglobulin levels were IgG < 70 mg/dL, IgA < 15 mg/dL, and IgM 24 mg/dL. Absolute lymphocyte count was in the low normal range for age at 3,869 cells/mm3. Flow cytometry showed a normal CD19þ cell count of 1,061 cell/mL and a low CD3þ cell count of 1,832 cells/mL. The patient was placed on antibiotic prophylaxis, but given