Immunology

Diffuse alveolar hemorrhage can complicate a large number of clinical conditions. It may present in different ways and may be life-threatening, and it poses an important challenge for the clinician.¹

Diffuse alveolar hemorrhage is an uncommon condition in which blood floods the alveoli, usually at multiple sites. It is also known as intrapulmonary hemorrhage, diffuse pulmonary hemorrhage, pulmonary alveolar hemorrhage, pulmonary capillary hemorrhage, alveolar bleeding, or microvascular pulmonary hemorrhage.

In this article we review the causes, clinical features, diagnostic criteria, treatment, and prognosis of diffuse alveolar hemorrhage.

CAUSES OF DIFFUSE ALVEOLAR HEMORRHAGE

THREE CHARACTERISTIC PATTERNS

In general, diffuse alveolar hemorrhage can occur in three characteristic patterns, which reflect the nature of the underlying vascular injury¹:

Diffuse alveolar hemorrhage associated with vasculitis or capillaritis. As described by Spencer⁴ 50 years ago, pulmonary capillaritis is the most frequent underlying histologic lesion described in diffuse alveolar hemorrhage. Neutrophils infiltrate the interalveolar and peri-bronchiolar septal vessels (pulmonary interstitium),⁵ leading to anatomic disruption of the capillaries (ie, impairment of the alveolocapillary barrier) and to extravasation of red blood cells into the alveoli and interstitium. Neutrophil apoptosis and fragmentation, with subsequent release of the intracellular proteolytic enzymes and reactive oxygen species, beget more inflammation, intra-alveolar neutrophilic nuclear dust, fibrin and inflammatory exudate, and fibrinoid necrosis of the interstitium.^6,7

‘Bland’ pulmonary hemorrhage (ie, without capillaritis or vasculitis). In this pattern, red blood cells leak into the alveoli without any evidence of inflammation or destruction of the alveolar capillaries, venules, and arterioles. The epithelial lesions are usually microscopic and are scattered geographically.

Diffuse alveolar hemorrhage associated with another process or condition (eg, diffuse alveolar damage, lymphangioleiomyomatosis, drug-induced lung injury, metastatic tumor to the lungs, mitral stenosis). Diffuse alveolar damage is the main underlying lesion of the acute respiratory distress syndrome and is characterized by formation of an intra-alveolar hyaline membrane, by interstitial edema with minimal inflammation, and, at times, by “secondary” diffuse alveolar hemorrhage. In this third category of diffuse alveolar hemorrhage, the underlying process causes alveolar hemorrhage by processes other than pulmonary vascular inflammation or direct extravasation of red cells.

THE CLINICAL PRESENTATION

The clinical presentation of diffuse alveolar hemorrhage may reflect either alveolar bleeding alone or features of the underlying cause (eg, hematuria in Wegener granulomatosis, arthritis in systemic lupus erythematosus). Hence, its recognition requires a high degree of suspicion.

Some patients present with severe acute respiratory distress requiring mechanical ventilation. However, dyspnea, cough, and fever are the common initial symptoms and are most often acute or subacute (ie, present for less than a week). The fever is usually due to the underlying cause, such as lupus.

Hemoptysis may be absent at the time of presentation in up to a third of patients because the total alveolar volume is large and can absorb large amounts of blood, without extending more proximally into the airways. Apparent hemoptysis, if present, must be differentiated from hematemesis or pseudohemoptysis (alveolar flooding with fluid that resembles blood, as in Serratia marcescens pneumonia, in which the reddish hue of the infecting organism can create the impression of alveolar bleeding).

DIAGNOSTIC EVALUATION

Generally speaking, dyspnea, cough, hemoptysis, and new alveolar infiltrates in conjunction with bloody bronchoalveolar lavage specimens (with numerous erythrocytes and siderophages) establish the diagnosis of diffuse alveolar hemorrhage. Surgical biopsy from the lung or another organ involved by an underlying condition is often necessary.

Physical examination

The physical findings are nonspecific and may reflect the underlying systemic vasculitis or collagen vascular disorder (eg, with accompanying rash, purpura, eye lesions, hepatosplenomegaly, or clubbing).

Imaging studies

Radiography may show new or old or both new and old patchy or diffuse alveolar opacities. Recurrent episodes of hemorrhage may lead to reticular interstitial opacities due to pulmonary fibrosis, usually with minimal (if any) honeycombing. Kerley B lines suggest mitral valve disease or pulmonary veno-occlusive disease as the cause of the hemorrhage.

Computed tomography may show areas of consolidation interspersed with areas of ground-glass attenuation and preserved, normal areas.

Currently, nuclear imaging such as gallium or tagged red blood cell studies have little role in evaluating diffuse alveolar hemorrhage. Other nuclear studies, geared to reveal breakdown of the microcirculatory integrity and extravasation of red blood cells out of the vessels, have also not been proven useful.

Evaluating pulmonary function

Diffuse alveolar hemorrhage may cause impairment of oxygen transfer and hypoxemia. In addition, it can cause several other abnormalities of pulmonary function.

Increased diffusing capacity. Because blood in the lungs can absorb inhaled carbon monoxide, the diffusing capacity for carbon monoxide (DLCO) may be distinctively increased. Serial increases in the DLCO may indicate progressive alveolar hemorrhage. However, the clinical instability of patients experiencing active alveolar bleeding precludes performing the DLCO measurement maneuvers, rendering the DLCO test relatively impractical.

Restrictive changes. Because recurrent episodes of diffuse alveolar hemorrhage can lead to interstitial fibrosis, restrictive changes—ie, decreased total lung capacity, decreased forced vital capacity (FVC), and preserved ratio of the forced expiratory volume in 1 second (FEV₁) to the FVC—may characterize diffuse alveolar hemorrhage.

Obstructive changes (less common). Less commonly, patients with diffuse alveolar hemorrhage may have spirometric changes indicating airflow obstruction—ie, decreased FEV₁ and decreased ratio of FEV₁ to FVC—possibly because neutrophilic infiltration from blood extravasation into the alveolar sacs causes release of reactive oxygen species and proteolytic enzymes, which in turn may cause small airway and parenchymal damage such as bronchiolitis and emphysema. A pattern of obstructive lung disease associated with recurrent diffuse alveolar hemorrhage should prompt consideration of an underlying condition that can cause airflow obstruction, such as sarcoidosis, microscopic polyangiitis, or Wegener granulomatosis, or, less commonly, lymphangioleiomyomatosis, histiocytosis X, pulmonary capillaritis, or sometimes idiopathic pulmonary hemosiderosis.

As an example of an unusual circumstance, we have described elsewhere a case of a woman with idiopathic pulmonary hemosiderosis with multiple episodes of diffuse alveolar hemorrhage and resultant emphysema.⁸ Radiographic images showed several very large cysts, one of which herniated through the incision site of an open lung biopsy.

Decreased exhaled nitric oxide. Though currently unavailable in most clinical pulmonary function laboratories, evaluation of exhaled gas or condensate may have value in diagnosing diffuse alveolar hemorrhage.⁹ Specifically, because increased intra-alveolar hemoglobin binds nitric oxide, as it does carbon monoxide, levels of exhaled nitric oxide may be decreased in diffuse alveolar hemorrhage. In contrast to the difficulty of measuring DLCO in patients with active alveolar bleeding or hemoptysis, analysis of exhaled gas is clinically feasible, making this a promising diagnostic test.

Laboratory evaluation

Hematologic assessment in patients with diffuse alveolar hemorrhage generally reveals:

• Acute or chronic anemia
• Leukocytosis
• Elevated erythrocyte sedimentation rate
• Elevated C-reactive protein level (particularly in patients whose alveolar hemorrhage is due to systemic disease or vasculitis, or both).

Renal abnormalities such as elevated blood urea nitrogen and serum creatinine or abnormal findings on urinalysis (with hematuria, proteinuria, and red blood cell casts indicating glomerulonephritis) can also occur, as diffuse alveolar hemorrhage may complicate several pulmonary-renal syndromes such as Goodpasture syndrome and Wegener granulomatosis.

 

 

Bronchoscopy

The diagnostic evaluation in diffuse alveolar hemorrhage usually includes bronchoscopic examination,¹⁰ which serves two purposes:

• To document alveolar hemorrhage by bronchoalveolar lavage and to exclude airway sources of bleeding by visual inspection
• To exclude an associated infection.

Based on experience with nonmassive hemoptysis of all causes (but not exclusively diffuse alveolar hemorrhage), the diagnostic yield of bronchoscopy is higher if the procedure is performed within the first 48 hours of symptoms rather than later. Evidence supporting diffuse alveolar hemorrhage is persistent (or even increasing) blood on three sequential lavage aliquots from a single affected area of the lung.

FINDING THE UNDERLYING CAUSE

Once the diagnosis of diffuse alveolar hemorrhage is established, the clinician must ascertain whether an underlying cause is present. Serologic studies may prove important, although the results are generally not available in a manner timely enough to guide immediate management.

When a pulmonary-renal syndrome is suggested by accompanying hematuria or renal dysfunction, antiglomerular basement membrane antibody and antineutrophil cytoplasmic antibody (ANCA) levels should be checked. Tests for complement fractions C3 and C4, anti-double-stranded DNA, and antiphospholipid antibodies should be ordered if an underlying condition such as lupus or antiphospholipid antibody syndrome is suspected (Table 2).¹¹

If the underlying cause remains elusive after a thorough clinical evaluation that includes imaging studies, serologic studies, and bronchoscopy, then surgical biopsy should be considered.¹ Which organ to biopsy (eg, lung, sinus, kidney) depends on the level of suspicion for a specific cause. For example, suspicion of Wegener granulomato-sis with hematuria or renal dysfunction might prompt renal biopsy. However, lung biopsy often needs to be performed with video-assisted thoracoscopy, especially when disease is confined to the lung (as in idiopathic pulmonary hemosiderosis or pauci-immune pulmonary capillaritis). Renal biopsy specimens should also undergo immunofluores-cence staining, which may reveal linear deposition of immunoglobulins and immune complexes along the basement membrane in patients with Goodpasture syndrome, or of granular deposits in patients with systemic lupus erythematosus.

TWO GENERAL CLINICAL SCENARIOS

In general, the clinician will be confronted by one of two scenarios: a patient with diffuse alveolar hemorrhage and associated systemic findings, or a patient with hemorrhage and no associated systemic findings.

Hemorrhage with associated systemic findings

Certain clues from the history raise suspicion of diffuse alveolar hemorrhage:

• Recent infection suggests Henoch-Schönlein purpura or cryoglobulinemic vasculitis
• Use of a possibly offending drug such as an anticoagulant, D-penicillamine (Cuprimine, Depen), nitrofurantoin (Furadantin, Macrobid, Macrodantin), amiodarone (Cordarone), propylthiouracil, cocaine, or sirolimus (Rapamune, Rapamycin)
• Exposure to toxic agents such as trimellitic anhydride, insecticides, and pesticides
• A known comorbid condition such as vasculitis, connective tissue disease, mitral valve disease, or solid organ or stem cell transplantation.

If asthma, eosinophilia, pulmonary infiltrates, and diffuse alveolar hemorrhage coexist, consideration should be given to Churg-Strauss syndrome. If sinus disease, skin manifestations, pulmonary parenchymal nodules, and cavitary lesions coexist with positivity for antiproteinase 3 c-ANCA and biopsy-proven granulomata, then Wegener granulomatosis should be considered. Similarly, diffuse alveolar hemorrhage with glomerulonephritis and skin manifestations, positivity for p-ANCA, and necrotizing nongranulomatous lesions on end-organ biopsy may lead to a diagnosis of microscopic polyangiitis. In a young smoker with glomeru-lonephritis and diffuse alveolar hemorrhage presenting as either bland alveolar hemorrhage or pulmonary capillaritis, Goodpasture syndrome or antiglomerular basement membrane antibody disease should be considered.

Hemorrhage with no associated systemic findings

When the above conditions have been considered but no suggestive findings are found, the following four conditions should be considered:

• Antiglomerular basement membrane antibody disease in limited pulmonary form or onset: positivity to the antibody with linear deposits in the lungs would be diagnostic in such a case
• Pulmonary-limited microscopic polyangiitis positive for p-ANCA (a positive anti-myeloperoxidase p-ANCA test makes the diagnosis)
• Pauci-immune isolated pulmonary capillaritis, when the biopsy shows evidence of neutrophilic pulmonary capillaritis
• Idiopathic pulmonary hemosiderosis, a diagnosis of exclusion, when the biopsy shows evidence of acute, subacute, and chronic bland diffuse alveolar hemorrhage and no evidence of vasculitis.

TREATMENT OF DIFFUSE ALVEOLAR HEMORRHAGE

Therapy for diffuse alveolar hemorrhage consists of treating both the autoimmune destruction of the alveolar capillary membrane and the underlying condition. Corticosteroids and immunosuppressive agents remain the gold standard for most patients. Recombinant-activated human factor VII seems to be a promising new therapy, although further evaluation is needed.

Immunosuppressive agents are the mainstay of therapy for diffuse alveolar hemorrhage, especially if associated with systemic or pulmonary vasculitis, Goodpasture syndrome, and connective tissue disorders. Most experts recommend intravenous methylprednisolone (Solu-Medrol) (up to 500 mg every 6 hours, although lower doses seem to have similar efficacy) for 4 or 5 days, followed by a gradual taper to maintenance doses of oral steroids.

In patients with pulmonary-renal syndrome, therapy should be started as soon as possible to prevent irreversible renal failure.

Besides corticosteroids, other immunosuppressive drugs such as cyclophosphamide (Cytoxan), azathioprine (Imuran), mycophenolate mofetil (CellCept), and etanercept (Enbrel) may be used in diffuse alveolar hemorrhage, especially when the condition is severe, when first-line therapy with corticosteroids has proven ineffective (generally not advised, unless the condition is mild) or when specific underlying causes are present (eg, Wegener granulomatosis, Goodpasture syndrome, systemic lupus erythematosus). Intravenous cyclophosphamide (2 mg/kg/day, adjusted to renal function) is generally the preferred adjunctive immunosuppressive drug and may be continued for several weeks or until adverse effects occur, such as blood marrow suppression, infection, or hematuria. Thereafter, most clinicians switch to consolidative or maintenance therapy with methotrexate or another agent.

Plasmapheresis is indicated for diffuse alveolar hemorrhage associated with Good-pasture syndrome or with other vasculitic processes in which the titers of pathogenetic immunoglobulins and immune complexes are very high: for example, ANCA-associated vasculitis with overwhelming endothelial injury and a hypercoagulable state. However, the merits of plasmapharesis in diffuse alveolar hemorrhage associated with conditions other than Goodpasture syndrome has not been evaluated in prospective studies.

It remains unclear whether intravenous immunoglobulin therapy adds to the treatment of diffuse alveolar hemorrhage due to vasculitis or other connective tissue disease.

Several case reports have reported successful use of recombinant activated human factor VII in treating alveolar hemorrhage due to allogeneic hematopoietic stem cell transplantation, ANCA-associated vasculitis, systemic lupus erythematosus, or antiphospholipid syndrome. If borne out by larger experience, recombinant activated human factor VII may gain more widespread use in diffuse alveolar hemorrhage.

Other possible management measures include supplemental oxygen, bronchodilators, reversal of any coagulopathy, intubation with bronchial tamponade, protective strategies for the less involved lung, and mechanical ventilation.

PROGNOSIS

The prognosis for diffuse alveolar hemorrhage depends on the underlying cause (Table 3).

Recurrent episodes may lead to various degrees of interstitial fibrosis, especially in patients with underlying Wegener granulo-matosis, mitral stenosis, long-standing and severe mitral regurgitation, and idiopathic pulmonary hemosiderosis. Obstructive lung disease may also complicate microscopic polyangiitis and idiopathic pulmonary hemosiderosis.
 

Acknowledgment: We acknowledge and appreciate the assistance of Dr. Carol Farver, who provided the pathologic specimens.

Diffuse alveolar hemorrhage can complicate a large number of clinical conditions. It may present in different ways and may be life-threatening, and it poses an important challenge for the clinician.¹

Diffuse alveolar hemorrhage is an uncommon condition in which blood floods the alveoli, usually at multiple sites. It is also known as intrapulmonary hemorrhage, diffuse pulmonary hemorrhage, pulmonary alveolar hemorrhage, pulmonary capillary hemorrhage, alveolar bleeding, or microvascular pulmonary hemorrhage.

In this article we review the causes, clinical features, diagnostic criteria, treatment, and prognosis of diffuse alveolar hemorrhage.

CAUSES OF DIFFUSE ALVEOLAR HEMORRHAGE

THREE CHARACTERISTIC PATTERNS

In general, diffuse alveolar hemorrhage can occur in three characteristic patterns, which reflect the nature of the underlying vascular injury¹:

Diffuse alveolar hemorrhage associated with vasculitis or capillaritis. As described by Spencer⁴ 50 years ago, pulmonary capillaritis is the most frequent underlying histologic lesion described in diffuse alveolar hemorrhage. Neutrophils infiltrate the interalveolar and peri-bronchiolar septal vessels (pulmonary interstitium),⁵ leading to anatomic disruption of the capillaries (ie, impairment of the alveolocapillary barrier) and to extravasation of red blood cells into the alveoli and interstitium. Neutrophil apoptosis and fragmentation, with subsequent release of the intracellular proteolytic enzymes and reactive oxygen species, beget more inflammation, intra-alveolar neutrophilic nuclear dust, fibrin and inflammatory exudate, and fibrinoid necrosis of the interstitium.^6,7

‘Bland’ pulmonary hemorrhage (ie, without capillaritis or vasculitis). In this pattern, red blood cells leak into the alveoli without any evidence of inflammation or destruction of the alveolar capillaries, venules, and arterioles. The epithelial lesions are usually microscopic and are scattered geographically.

Diffuse alveolar hemorrhage associated with another process or condition (eg, diffuse alveolar damage, lymphangioleiomyomatosis, drug-induced lung injury, metastatic tumor to the lungs, mitral stenosis). Diffuse alveolar damage is the main underlying lesion of the acute respiratory distress syndrome and is characterized by formation of an intra-alveolar hyaline membrane, by interstitial edema with minimal inflammation, and, at times, by “secondary” diffuse alveolar hemorrhage. In this third category of diffuse alveolar hemorrhage, the underlying process causes alveolar hemorrhage by processes other than pulmonary vascular inflammation or direct extravasation of red cells.

THE CLINICAL PRESENTATION

The clinical presentation of diffuse alveolar hemorrhage may reflect either alveolar bleeding alone or features of the underlying cause (eg, hematuria in Wegener granulomatosis, arthritis in systemic lupus erythematosus). Hence, its recognition requires a high degree of suspicion.

Some patients present with severe acute respiratory distress requiring mechanical ventilation. However, dyspnea, cough, and fever are the common initial symptoms and are most often acute or subacute (ie, present for less than a week). The fever is usually due to the underlying cause, such as lupus.

Hemoptysis may be absent at the time of presentation in up to a third of patients because the total alveolar volume is large and can absorb large amounts of blood, without extending more proximally into the airways. Apparent hemoptysis, if present, must be differentiated from hematemesis or pseudohemoptysis (alveolar flooding with fluid that resembles blood, as in Serratia marcescens pneumonia, in which the reddish hue of the infecting organism can create the impression of alveolar bleeding).

DIAGNOSTIC EVALUATION

Generally speaking, dyspnea, cough, hemoptysis, and new alveolar infiltrates in conjunction with bloody bronchoalveolar lavage specimens (with numerous erythrocytes and siderophages) establish the diagnosis of diffuse alveolar hemorrhage. Surgical biopsy from the lung or another organ involved by an underlying condition is often necessary.

Physical examination

The physical findings are nonspecific and may reflect the underlying systemic vasculitis or collagen vascular disorder (eg, with accompanying rash, purpura, eye lesions, hepatosplenomegaly, or clubbing).

Imaging studies

Radiography may show new or old or both new and old patchy or diffuse alveolar opacities. Recurrent episodes of hemorrhage may lead to reticular interstitial opacities due to pulmonary fibrosis, usually with minimal (if any) honeycombing. Kerley B lines suggest mitral valve disease or pulmonary veno-occlusive disease as the cause of the hemorrhage.

Computed tomography may show areas of consolidation interspersed with areas of ground-glass attenuation and preserved, normal areas.

Currently, nuclear imaging such as gallium or tagged red blood cell studies have little role in evaluating diffuse alveolar hemorrhage. Other nuclear studies, geared to reveal breakdown of the microcirculatory integrity and extravasation of red blood cells out of the vessels, have also not been proven useful.

Evaluating pulmonary function

Diffuse alveolar hemorrhage may cause impairment of oxygen transfer and hypoxemia. In addition, it can cause several other abnormalities of pulmonary function.

Increased diffusing capacity. Because blood in the lungs can absorb inhaled carbon monoxide, the diffusing capacity for carbon monoxide (DLCO) may be distinctively increased. Serial increases in the DLCO may indicate progressive alveolar hemorrhage. However, the clinical instability of patients experiencing active alveolar bleeding precludes performing the DLCO measurement maneuvers, rendering the DLCO test relatively impractical.

Restrictive changes. Because recurrent episodes of diffuse alveolar hemorrhage can lead to interstitial fibrosis, restrictive changes—ie, decreased total lung capacity, decreased forced vital capacity (FVC), and preserved ratio of the forced expiratory volume in 1 second (FEV₁) to the FVC—may characterize diffuse alveolar hemorrhage.

Obstructive changes (less common). Less commonly, patients with diffuse alveolar hemorrhage may have spirometric changes indicating airflow obstruction—ie, decreased FEV₁ and decreased ratio of FEV₁ to FVC—possibly because neutrophilic infiltration from blood extravasation into the alveolar sacs causes release of reactive oxygen species and proteolytic enzymes, which in turn may cause small airway and parenchymal damage such as bronchiolitis and emphysema. A pattern of obstructive lung disease associated with recurrent diffuse alveolar hemorrhage should prompt consideration of an underlying condition that can cause airflow obstruction, such as sarcoidosis, microscopic polyangiitis, or Wegener granulomatosis, or, less commonly, lymphangioleiomyomatosis, histiocytosis X, pulmonary capillaritis, or sometimes idiopathic pulmonary hemosiderosis.

As an example of an unusual circumstance, we have described elsewhere a case of a woman with idiopathic pulmonary hemosiderosis with multiple episodes of diffuse alveolar hemorrhage and resultant emphysema.⁸ Radiographic images showed several very large cysts, one of which herniated through the incision site of an open lung biopsy.

Decreased exhaled nitric oxide. Though currently unavailable in most clinical pulmonary function laboratories, evaluation of exhaled gas or condensate may have value in diagnosing diffuse alveolar hemorrhage.⁹ Specifically, because increased intra-alveolar hemoglobin binds nitric oxide, as it does carbon monoxide, levels of exhaled nitric oxide may be decreased in diffuse alveolar hemorrhage. In contrast to the difficulty of measuring DLCO in patients with active alveolar bleeding or hemoptysis, analysis of exhaled gas is clinically feasible, making this a promising diagnostic test.

Laboratory evaluation

Hematologic assessment in patients with diffuse alveolar hemorrhage generally reveals:

• Acute or chronic anemia
• Leukocytosis
• Elevated erythrocyte sedimentation rate
• Elevated C-reactive protein level (particularly in patients whose alveolar hemorrhage is due to systemic disease or vasculitis, or both).

Renal abnormalities such as elevated blood urea nitrogen and serum creatinine or abnormal findings on urinalysis (with hematuria, proteinuria, and red blood cell casts indicating glomerulonephritis) can also occur, as diffuse alveolar hemorrhage may complicate several pulmonary-renal syndromes such as Goodpasture syndrome and Wegener granulomatosis.

 

 

Bronchoscopy

The diagnostic evaluation in diffuse alveolar hemorrhage usually includes bronchoscopic examination,¹⁰ which serves two purposes:

• To document alveolar hemorrhage by bronchoalveolar lavage and to exclude airway sources of bleeding by visual inspection
• To exclude an associated infection.

Based on experience with nonmassive hemoptysis of all causes (but not exclusively diffuse alveolar hemorrhage), the diagnostic yield of bronchoscopy is higher if the procedure is performed within the first 48 hours of symptoms rather than later. Evidence supporting diffuse alveolar hemorrhage is persistent (or even increasing) blood on three sequential lavage aliquots from a single affected area of the lung.

FINDING THE UNDERLYING CAUSE

Once the diagnosis of diffuse alveolar hemorrhage is established, the clinician must ascertain whether an underlying cause is present. Serologic studies may prove important, although the results are generally not available in a manner timely enough to guide immediate management.

When a pulmonary-renal syndrome is suggested by accompanying hematuria or renal dysfunction, antiglomerular basement membrane antibody and antineutrophil cytoplasmic antibody (ANCA) levels should be checked. Tests for complement fractions C3 and C4, anti-double-stranded DNA, and antiphospholipid antibodies should be ordered if an underlying condition such as lupus or antiphospholipid antibody syndrome is suspected (Table 2).¹¹

If the underlying cause remains elusive after a thorough clinical evaluation that includes imaging studies, serologic studies, and bronchoscopy, then surgical biopsy should be considered.¹ Which organ to biopsy (eg, lung, sinus, kidney) depends on the level of suspicion for a specific cause. For example, suspicion of Wegener granulomato-sis with hematuria or renal dysfunction might prompt renal biopsy. However, lung biopsy often needs to be performed with video-assisted thoracoscopy, especially when disease is confined to the lung (as in idiopathic pulmonary hemosiderosis or pauci-immune pulmonary capillaritis). Renal biopsy specimens should also undergo immunofluores-cence staining, which may reveal linear deposition of immunoglobulins and immune complexes along the basement membrane in patients with Goodpasture syndrome, or of granular deposits in patients with systemic lupus erythematosus.

TWO GENERAL CLINICAL SCENARIOS

In general, the clinician will be confronted by one of two scenarios: a patient with diffuse alveolar hemorrhage and associated systemic findings, or a patient with hemorrhage and no associated systemic findings.

Hemorrhage with associated systemic findings

Certain clues from the history raise suspicion of diffuse alveolar hemorrhage:

• Recent infection suggests Henoch-Schönlein purpura or cryoglobulinemic vasculitis
• Use of a possibly offending drug such as an anticoagulant, D-penicillamine (Cuprimine, Depen), nitrofurantoin (Furadantin, Macrobid, Macrodantin), amiodarone (Cordarone), propylthiouracil, cocaine, or sirolimus (Rapamune, Rapamycin)
• Exposure to toxic agents such as trimellitic anhydride, insecticides, and pesticides
• A known comorbid condition such as vasculitis, connective tissue disease, mitral valve disease, or solid organ or stem cell transplantation.

If asthma, eosinophilia, pulmonary infiltrates, and diffuse alveolar hemorrhage coexist, consideration should be given to Churg-Strauss syndrome. If sinus disease, skin manifestations, pulmonary parenchymal nodules, and cavitary lesions coexist with positivity for antiproteinase 3 c-ANCA and biopsy-proven granulomata, then Wegener granulomatosis should be considered. Similarly, diffuse alveolar hemorrhage with glomerulonephritis and skin manifestations, positivity for p-ANCA, and necrotizing nongranulomatous lesions on end-organ biopsy may lead to a diagnosis of microscopic polyangiitis. In a young smoker with glomeru-lonephritis and diffuse alveolar hemorrhage presenting as either bland alveolar hemorrhage or pulmonary capillaritis, Goodpasture syndrome or antiglomerular basement membrane antibody disease should be considered.

Hemorrhage with no associated systemic findings

When the above conditions have been considered but no suggestive findings are found, the following four conditions should be considered:

• Antiglomerular basement membrane antibody disease in limited pulmonary form or onset: positivity to the antibody with linear deposits in the lungs would be diagnostic in such a case
• Pulmonary-limited microscopic polyangiitis positive for p-ANCA (a positive anti-myeloperoxidase p-ANCA test makes the diagnosis)
• Pauci-immune isolated pulmonary capillaritis, when the biopsy shows evidence of neutrophilic pulmonary capillaritis
• Idiopathic pulmonary hemosiderosis, a diagnosis of exclusion, when the biopsy shows evidence of acute, subacute, and chronic bland diffuse alveolar hemorrhage and no evidence of vasculitis.

TREATMENT OF DIFFUSE ALVEOLAR HEMORRHAGE

Therapy for diffuse alveolar hemorrhage consists of treating both the autoimmune destruction of the alveolar capillary membrane and the underlying condition. Corticosteroids and immunosuppressive agents remain the gold standard for most patients. Recombinant-activated human factor VII seems to be a promising new therapy, although further evaluation is needed.

Immunosuppressive agents are the mainstay of therapy for diffuse alveolar hemorrhage, especially if associated with systemic or pulmonary vasculitis, Goodpasture syndrome, and connective tissue disorders. Most experts recommend intravenous methylprednisolone (Solu-Medrol) (up to 500 mg every 6 hours, although lower doses seem to have similar efficacy) for 4 or 5 days, followed by a gradual taper to maintenance doses of oral steroids.

In patients with pulmonary-renal syndrome, therapy should be started as soon as possible to prevent irreversible renal failure.

Besides corticosteroids, other immunosuppressive drugs such as cyclophosphamide (Cytoxan), azathioprine (Imuran), mycophenolate mofetil (CellCept), and etanercept (Enbrel) may be used in diffuse alveolar hemorrhage, especially when the condition is severe, when first-line therapy with corticosteroids has proven ineffective (generally not advised, unless the condition is mild) or when specific underlying causes are present (eg, Wegener granulomatosis, Goodpasture syndrome, systemic lupus erythematosus). Intravenous cyclophosphamide (2 mg/kg/day, adjusted to renal function) is generally the preferred adjunctive immunosuppressive drug and may be continued for several weeks or until adverse effects occur, such as blood marrow suppression, infection, or hematuria. Thereafter, most clinicians switch to consolidative or maintenance therapy with methotrexate or another agent.

Plasmapheresis is indicated for diffuse alveolar hemorrhage associated with Good-pasture syndrome or with other vasculitic processes in which the titers of pathogenetic immunoglobulins and immune complexes are very high: for example, ANCA-associated vasculitis with overwhelming endothelial injury and a hypercoagulable state. However, the merits of plasmapharesis in diffuse alveolar hemorrhage associated with conditions other than Goodpasture syndrome has not been evaluated in prospective studies.

It remains unclear whether intravenous immunoglobulin therapy adds to the treatment of diffuse alveolar hemorrhage due to vasculitis or other connective tissue disease.

Several case reports have reported successful use of recombinant activated human factor VII in treating alveolar hemorrhage due to allogeneic hematopoietic stem cell transplantation, ANCA-associated vasculitis, systemic lupus erythematosus, or antiphospholipid syndrome. If borne out by larger experience, recombinant activated human factor VII may gain more widespread use in diffuse alveolar hemorrhage.

Other possible management measures include supplemental oxygen, bronchodilators, reversal of any coagulopathy, intubation with bronchial tamponade, protective strategies for the less involved lung, and mechanical ventilation.

PROGNOSIS

The prognosis for diffuse alveolar hemorrhage depends on the underlying cause (Table 3).

Recurrent episodes may lead to various degrees of interstitial fibrosis, especially in patients with underlying Wegener granulo-matosis, mitral stenosis, long-standing and severe mitral regurgitation, and idiopathic pulmonary hemosiderosis. Obstructive lung disease may also complicate microscopic polyangiitis and idiopathic pulmonary hemosiderosis.
 

Acknowledgment: We acknowledge and appreciate the assistance of Dr. Carol Farver, who provided the pathologic specimens.

Diffuse alveolar hemorrhage can complicate a large number of clinical conditions. It may present in different ways and may be life-threatening, and it poses an important challenge for the clinician.¹

Diffuse alveolar hemorrhage is an uncommon condition in which blood floods the alveoli, usually at multiple sites. It is also known as intrapulmonary hemorrhage, diffuse pulmonary hemorrhage, pulmonary alveolar hemorrhage, pulmonary capillary hemorrhage, alveolar bleeding, or microvascular pulmonary hemorrhage.

In this article we review the causes, clinical features, diagnostic criteria, treatment, and prognosis of diffuse alveolar hemorrhage.

CAUSES OF DIFFUSE ALVEOLAR HEMORRHAGE

THREE CHARACTERISTIC PATTERNS

In general, diffuse alveolar hemorrhage can occur in three characteristic patterns, which reflect the nature of the underlying vascular injury¹:

Diffuse alveolar hemorrhage associated with vasculitis or capillaritis. As described by Spencer⁴ 50 years ago, pulmonary capillaritis is the most frequent underlying histologic lesion described in diffuse alveolar hemorrhage. Neutrophils infiltrate the interalveolar and peri-bronchiolar septal vessels (pulmonary interstitium),⁵ leading to anatomic disruption of the capillaries (ie, impairment of the alveolocapillary barrier) and to extravasation of red blood cells into the alveoli and interstitium. Neutrophil apoptosis and fragmentation, with subsequent release of the intracellular proteolytic enzymes and reactive oxygen species, beget more inflammation, intra-alveolar neutrophilic nuclear dust, fibrin and inflammatory exudate, and fibrinoid necrosis of the interstitium.^6,7

‘Bland’ pulmonary hemorrhage (ie, without capillaritis or vasculitis). In this pattern, red blood cells leak into the alveoli without any evidence of inflammation or destruction of the alveolar capillaries, venules, and arterioles. The epithelial lesions are usually microscopic and are scattered geographically.

Diffuse alveolar hemorrhage associated with another process or condition (eg, diffuse alveolar damage, lymphangioleiomyomatosis, drug-induced lung injury, metastatic tumor to the lungs, mitral stenosis). Diffuse alveolar damage is the main underlying lesion of the acute respiratory distress syndrome and is characterized by formation of an intra-alveolar hyaline membrane, by interstitial edema with minimal inflammation, and, at times, by “secondary” diffuse alveolar hemorrhage. In this third category of diffuse alveolar hemorrhage, the underlying process causes alveolar hemorrhage by processes other than pulmonary vascular inflammation or direct extravasation of red cells.

THE CLINICAL PRESENTATION

The clinical presentation of diffuse alveolar hemorrhage may reflect either alveolar bleeding alone or features of the underlying cause (eg, hematuria in Wegener granulomatosis, arthritis in systemic lupus erythematosus). Hence, its recognition requires a high degree of suspicion.

Some patients present with severe acute respiratory distress requiring mechanical ventilation. However, dyspnea, cough, and fever are the common initial symptoms and are most often acute or subacute (ie, present for less than a week). The fever is usually due to the underlying cause, such as lupus.

Hemoptysis may be absent at the time of presentation in up to a third of patients because the total alveolar volume is large and can absorb large amounts of blood, without extending more proximally into the airways. Apparent hemoptysis, if present, must be differentiated from hematemesis or pseudohemoptysis (alveolar flooding with fluid that resembles blood, as in Serratia marcescens pneumonia, in which the reddish hue of the infecting organism can create the impression of alveolar bleeding).

DIAGNOSTIC EVALUATION

Generally speaking, dyspnea, cough, hemoptysis, and new alveolar infiltrates in conjunction with bloody bronchoalveolar lavage specimens (with numerous erythrocytes and siderophages) establish the diagnosis of diffuse alveolar hemorrhage. Surgical biopsy from the lung or another organ involved by an underlying condition is often necessary.

Physical examination

The physical findings are nonspecific and may reflect the underlying systemic vasculitis or collagen vascular disorder (eg, with accompanying rash, purpura, eye lesions, hepatosplenomegaly, or clubbing).

Imaging studies

Radiography may show new or old or both new and old patchy or diffuse alveolar opacities. Recurrent episodes of hemorrhage may lead to reticular interstitial opacities due to pulmonary fibrosis, usually with minimal (if any) honeycombing. Kerley B lines suggest mitral valve disease or pulmonary veno-occlusive disease as the cause of the hemorrhage.

Computed tomography may show areas of consolidation interspersed with areas of ground-glass attenuation and preserved, normal areas.

Currently, nuclear imaging such as gallium or tagged red blood cell studies have little role in evaluating diffuse alveolar hemorrhage. Other nuclear studies, geared to reveal breakdown of the microcirculatory integrity and extravasation of red blood cells out of the vessels, have also not been proven useful.

Evaluating pulmonary function

Diffuse alveolar hemorrhage may cause impairment of oxygen transfer and hypoxemia. In addition, it can cause several other abnormalities of pulmonary function.

Increased diffusing capacity. Because blood in the lungs can absorb inhaled carbon monoxide, the diffusing capacity for carbon monoxide (DLCO) may be distinctively increased. Serial increases in the DLCO may indicate progressive alveolar hemorrhage. However, the clinical instability of patients experiencing active alveolar bleeding precludes performing the DLCO measurement maneuvers, rendering the DLCO test relatively impractical.

Restrictive changes. Because recurrent episodes of diffuse alveolar hemorrhage can lead to interstitial fibrosis, restrictive changes—ie, decreased total lung capacity, decreased forced vital capacity (FVC), and preserved ratio of the forced expiratory volume in 1 second (FEV₁) to the FVC—may characterize diffuse alveolar hemorrhage.

Obstructive changes (less common). Less commonly, patients with diffuse alveolar hemorrhage may have spirometric changes indicating airflow obstruction—ie, decreased FEV₁ and decreased ratio of FEV₁ to FVC—possibly because neutrophilic infiltration from blood extravasation into the alveolar sacs causes release of reactive oxygen species and proteolytic enzymes, which in turn may cause small airway and parenchymal damage such as bronchiolitis and emphysema. A pattern of obstructive lung disease associated with recurrent diffuse alveolar hemorrhage should prompt consideration of an underlying condition that can cause airflow obstruction, such as sarcoidosis, microscopic polyangiitis, or Wegener granulomatosis, or, less commonly, lymphangioleiomyomatosis, histiocytosis X, pulmonary capillaritis, or sometimes idiopathic pulmonary hemosiderosis.

As an example of an unusual circumstance, we have described elsewhere a case of a woman with idiopathic pulmonary hemosiderosis with multiple episodes of diffuse alveolar hemorrhage and resultant emphysema.⁸ Radiographic images showed several very large cysts, one of which herniated through the incision site of an open lung biopsy.

Decreased exhaled nitric oxide. Though currently unavailable in most clinical pulmonary function laboratories, evaluation of exhaled gas or condensate may have value in diagnosing diffuse alveolar hemorrhage.⁹ Specifically, because increased intra-alveolar hemoglobin binds nitric oxide, as it does carbon monoxide, levels of exhaled nitric oxide may be decreased in diffuse alveolar hemorrhage. In contrast to the difficulty of measuring DLCO in patients with active alveolar bleeding or hemoptysis, analysis of exhaled gas is clinically feasible, making this a promising diagnostic test.

Laboratory evaluation

Hematologic assessment in patients with diffuse alveolar hemorrhage generally reveals:

• Acute or chronic anemia
• Leukocytosis
• Elevated erythrocyte sedimentation rate
• Elevated C-reactive protein level (particularly in patients whose alveolar hemorrhage is due to systemic disease or vasculitis, or both).

Renal abnormalities such as elevated blood urea nitrogen and serum creatinine or abnormal findings on urinalysis (with hematuria, proteinuria, and red blood cell casts indicating glomerulonephritis) can also occur, as diffuse alveolar hemorrhage may complicate several pulmonary-renal syndromes such as Goodpasture syndrome and Wegener granulomatosis.

 

 

Bronchoscopy

The diagnostic evaluation in diffuse alveolar hemorrhage usually includes bronchoscopic examination,¹⁰ which serves two purposes:

• To document alveolar hemorrhage by bronchoalveolar lavage and to exclude airway sources of bleeding by visual inspection
• To exclude an associated infection.

Based on experience with nonmassive hemoptysis of all causes (but not exclusively diffuse alveolar hemorrhage), the diagnostic yield of bronchoscopy is higher if the procedure is performed within the first 48 hours of symptoms rather than later. Evidence supporting diffuse alveolar hemorrhage is persistent (or even increasing) blood on three sequential lavage aliquots from a single affected area of the lung.

FINDING THE UNDERLYING CAUSE

Once the diagnosis of diffuse alveolar hemorrhage is established, the clinician must ascertain whether an underlying cause is present. Serologic studies may prove important, although the results are generally not available in a manner timely enough to guide immediate management.

When a pulmonary-renal syndrome is suggested by accompanying hematuria or renal dysfunction, antiglomerular basement membrane antibody and antineutrophil cytoplasmic antibody (ANCA) levels should be checked. Tests for complement fractions C3 and C4, anti-double-stranded DNA, and antiphospholipid antibodies should be ordered if an underlying condition such as lupus or antiphospholipid antibody syndrome is suspected (Table 2).¹¹

If the underlying cause remains elusive after a thorough clinical evaluation that includes imaging studies, serologic studies, and bronchoscopy, then surgical biopsy should be considered.¹ Which organ to biopsy (eg, lung, sinus, kidney) depends on the level of suspicion for a specific cause. For example, suspicion of Wegener granulomato-sis with hematuria or renal dysfunction might prompt renal biopsy. However, lung biopsy often needs to be performed with video-assisted thoracoscopy, especially when disease is confined to the lung (as in idiopathic pulmonary hemosiderosis or pauci-immune pulmonary capillaritis). Renal biopsy specimens should also undergo immunofluores-cence staining, which may reveal linear deposition of immunoglobulins and immune complexes along the basement membrane in patients with Goodpasture syndrome, or of granular deposits in patients with systemic lupus erythematosus.

TWO GENERAL CLINICAL SCENARIOS

In general, the clinician will be confronted by one of two scenarios: a patient with diffuse alveolar hemorrhage and associated systemic findings, or a patient with hemorrhage and no associated systemic findings.

Hemorrhage with associated systemic findings

Certain clues from the history raise suspicion of diffuse alveolar hemorrhage:

• Recent infection suggests Henoch-Schönlein purpura or cryoglobulinemic vasculitis
• Use of a possibly offending drug such as an anticoagulant, D-penicillamine (Cuprimine, Depen), nitrofurantoin (Furadantin, Macrobid, Macrodantin), amiodarone (Cordarone), propylthiouracil, cocaine, or sirolimus (Rapamune, Rapamycin)
• Exposure to toxic agents such as trimellitic anhydride, insecticides, and pesticides
• A known comorbid condition such as vasculitis, connective tissue disease, mitral valve disease, or solid organ or stem cell transplantation.

If asthma, eosinophilia, pulmonary infiltrates, and diffuse alveolar hemorrhage coexist, consideration should be given to Churg-Strauss syndrome. If sinus disease, skin manifestations, pulmonary parenchymal nodules, and cavitary lesions coexist with positivity for antiproteinase 3 c-ANCA and biopsy-proven granulomata, then Wegener granulomatosis should be considered. Similarly, diffuse alveolar hemorrhage with glomerulonephritis and skin manifestations, positivity for p-ANCA, and necrotizing nongranulomatous lesions on end-organ biopsy may lead to a diagnosis of microscopic polyangiitis. In a young smoker with glomeru-lonephritis and diffuse alveolar hemorrhage presenting as either bland alveolar hemorrhage or pulmonary capillaritis, Goodpasture syndrome or antiglomerular basement membrane antibody disease should be considered.

Hemorrhage with no associated systemic findings

When the above conditions have been considered but no suggestive findings are found, the following four conditions should be considered:

• Antiglomerular basement membrane antibody disease in limited pulmonary form or onset: positivity to the antibody with linear deposits in the lungs would be diagnostic in such a case
• Pulmonary-limited microscopic polyangiitis positive for p-ANCA (a positive anti-myeloperoxidase p-ANCA test makes the diagnosis)
• Pauci-immune isolated pulmonary capillaritis, when the biopsy shows evidence of neutrophilic pulmonary capillaritis
• Idiopathic pulmonary hemosiderosis, a diagnosis of exclusion, when the biopsy shows evidence of acute, subacute, and chronic bland diffuse alveolar hemorrhage and no evidence of vasculitis.

TREATMENT OF DIFFUSE ALVEOLAR HEMORRHAGE

Therapy for diffuse alveolar hemorrhage consists of treating both the autoimmune destruction of the alveolar capillary membrane and the underlying condition. Corticosteroids and immunosuppressive agents remain the gold standard for most patients. Recombinant-activated human factor VII seems to be a promising new therapy, although further evaluation is needed.

Immunosuppressive agents are the mainstay of therapy for diffuse alveolar hemorrhage, especially if associated with systemic or pulmonary vasculitis, Goodpasture syndrome, and connective tissue disorders. Most experts recommend intravenous methylprednisolone (Solu-Medrol) (up to 500 mg every 6 hours, although lower doses seem to have similar efficacy) for 4 or 5 days, followed by a gradual taper to maintenance doses of oral steroids.

In patients with pulmonary-renal syndrome, therapy should be started as soon as possible to prevent irreversible renal failure.

Besides corticosteroids, other immunosuppressive drugs such as cyclophosphamide (Cytoxan), azathioprine (Imuran), mycophenolate mofetil (CellCept), and etanercept (Enbrel) may be used in diffuse alveolar hemorrhage, especially when the condition is severe, when first-line therapy with corticosteroids has proven ineffective (generally not advised, unless the condition is mild) or when specific underlying causes are present (eg, Wegener granulomatosis, Goodpasture syndrome, systemic lupus erythematosus). Intravenous cyclophosphamide (2 mg/kg/day, adjusted to renal function) is generally the preferred adjunctive immunosuppressive drug and may be continued for several weeks or until adverse effects occur, such as blood marrow suppression, infection, or hematuria. Thereafter, most clinicians switch to consolidative or maintenance therapy with methotrexate or another agent.

Plasmapheresis is indicated for diffuse alveolar hemorrhage associated with Good-pasture syndrome or with other vasculitic processes in which the titers of pathogenetic immunoglobulins and immune complexes are very high: for example, ANCA-associated vasculitis with overwhelming endothelial injury and a hypercoagulable state. However, the merits of plasmapharesis in diffuse alveolar hemorrhage associated with conditions other than Goodpasture syndrome has not been evaluated in prospective studies.

It remains unclear whether intravenous immunoglobulin therapy adds to the treatment of diffuse alveolar hemorrhage due to vasculitis or other connective tissue disease.

Several case reports have reported successful use of recombinant activated human factor VII in treating alveolar hemorrhage due to allogeneic hematopoietic stem cell transplantation, ANCA-associated vasculitis, systemic lupus erythematosus, or antiphospholipid syndrome. If borne out by larger experience, recombinant activated human factor VII may gain more widespread use in diffuse alveolar hemorrhage.

Other possible management measures include supplemental oxygen, bronchodilators, reversal of any coagulopathy, intubation with bronchial tamponade, protective strategies for the less involved lung, and mechanical ventilation.

PROGNOSIS

The prognosis for diffuse alveolar hemorrhage depends on the underlying cause (Table 3).

Recurrent episodes may lead to various degrees of interstitial fibrosis, especially in patients with underlying Wegener granulo-matosis, mitral stenosis, long-standing and severe mitral regurgitation, and idiopathic pulmonary hemosiderosis. Obstructive lung disease may also complicate microscopic polyangiitis and idiopathic pulmonary hemosiderosis.
 

Acknowledgment: We acknowledge and appreciate the assistance of Dr. Carol Farver, who provided the pathologic specimens.

ILLUSTRATIVE CASE

A 39-year-old, otherwise healthy woman presents to your clinic with a sore throat, nasal congestion, and dry cough she’s had since yesterday. She wants an antibiotic, but your evaluation reveals an uncomplicated viral upper respiratory infection—a common cold. You would like to provide her with an alternative treatment, but you are aware of the lack of evidence for clear benefit of zinc lozenges, echinacea, and vitamin C. Is there any other medication that might benefit this patient?

Yes. Pelargonium sidoides, a species of South African geranium used for centuries in Zulu medicine,² shows promise as an herbal remedy for respiratory infections. Two randomized trials show that extracts of P sidoides improve symptoms of acute bronchitis which, like the common cold, is usually caused by a virus.^3-5

There is a plausible biological mechanism of action. In vitro studies show that Pelargonium extract induces the interferon system and up-regulates cytokines important in protecting host cells from viral infection.⁶

BACKGROUND: $17 billion dollar cold

Our patients want more relief from cold symptoms and are clearly willing to pay for it. Americans spend approximately $2.9 billion annually on over-the-counter (OTC) cold preparations and $1.1 billion on unnecessary antibiotics.⁷ The term “common cold” refers to a collection of symptoms, including sore throat, rhinorrhea, nasal congestion, cough, low-grade fever, and malaise, usually self-limited and lasting 10 to 14 days, caused by a number of viruses, most commonly by a rhinovirus.⁸ According to the 2005 National Ambulatory Medical Care Survey, the common cold is the third most common diagnosis in physicians’ offices behind only hypertension and well-infant/child visits.⁹ A 2001 US telephone survey determined that approximately 500 million episodes of non-influenza viral infection occur annually, resulting in direct costs of $17 billion for physician services and medications and approximately 200 million missed days of work.⁷

CLINICAL CONTEXT: Evidence proves most cold remedies don’t work

Although colds are common and result in annoying symptoms and missed work, much of the money spent on remedies is wasted. A truly effective treatment would be valuable to our patients.

Despite brisk sales, evidence for the efficacy of various cold remedies is inconclusive and contradictory. We found 6 Cochrane reviews of cold treatments, including antitussives, antihistamines, decongestants, vitamin C, echinacea, and zinc lozenges. With the exception of pseudoephedrine for nasal symptoms, the evidence that any product improves symptoms or decreases the duration of the cold is not encouraging.

Cough medications. The 2004 Cochrane Review of OTC medications for cough¹⁰ found no consistent evidence that any of them work. Codeine was no more effective than placebo for reducing cough symptoms. Three efficacy studies of dextromethorphan for cough showed either no difference or small but possibly clinically insignificant improvement in cough over placebo. One study of guaifenesin showed benefit over placebo in reducing cough frequency; another one showed no benefit over placebo.

Vitamin C, echinacea. Three Cochrane reviews found no conclusive evidence of benefit over placebo for either vitamin C¹¹ or echinacea¹² in treating the common cold.

Zinc. A new panel has been convened by the Cochrane group to reassess the effectiveness of zinc, but a 1999 Cochrane review¹³ found no benefit for zinc over placebo.

Antihistamines are not effective for relieving cold symptoms.¹⁴

Pseudoephedrine is the only medication with good-quality evidence for effectiveness, but only for reducing nasal symptoms.¹⁵ The authors concluded that patients may be encouraged to continue pseudoephedrine for up to 5 days if found to be effective with the first dose. Nasal congestion and discharge, however, are only 2 of the many irritating symptoms of a cold.

You can be a “REALITY CHECKER”

Bernard Ewigman, MD, MSPH

If you are in full-time clinical practice, a medical director of a practice, or otherwise directly involved in decision-making about adopting new practices, join our team of “reality checkers.”

Just email me at be.editor@gmail.com

STUDY SUMMARY: Duration and severity of symptoms are reduced

This was a multicenter, prospective, double-blind, placebo-controlled randomized trial to evaluate the effectiveness of a liquid herbal preparation from the roots of Pelargonium sidoides for decreasing the duration and severity of symptoms of the common cold.

Patient characteristics. Patients were recruited from 8 outpatient departments in Ukraine between December 2003 and May 2004. Two hundred and seven (207) patients were eligible. The number of ineligible and excluded patients was not stated. These 207 patients were randomized into 1 of 4 groups:

• 52 received 30 drops 3 times daily vs 51 patients who received placebo
• 52 patients received 60 drops 3 times daily vs 52 patients who received a higher-dose placebo.

The report gives the outcomes of the low-dose arm only. Two-thirds of the participants were women; all were Caucasian. Patients in the treatment and placebo groups were similar in terms of recurrent disease, prior use of medication for the common cold, smoking, and alcohol and caffeine consumption. All had a negative Group A beta-hemolytic strep test.

Inclusion criteria. Patients included men and women 18 to 55 years of age; able to provide written informed consent; with 2 major cold symptoms (nasal discharge, sore throat) and at least 1 minor cold symptom (nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, or fever) or presence of 1 major cold symptom and at least 3 minor cold symptoms; duration of symptoms 24 to 48 hours.

Exclusion criteria were any acute ear, nose, throat and respiratory tract disease other than the common cold; positive rapid strep test; 6 or more episodes of recurrent tonsillitis, sinusitis, or otitis within the past 12 months or any chronic ear, nose, throat or respiratory tract disease; treatment with antibiotics, glucocorticoids, or antihistamine drugs during the 4 weeks prior to enrollment in the trial; treatment with cold medications that might impair the trial results (eg, decongestants, local anesthetics); and use of cough or pain relief medications, or any other treatment for the common cold within 7 days prior to enrollment in the trial.

Treatment regimen. Patients were assigned to take 30 drops of either the study herbal preparation or 30 drops of placebo 3 times daily, at least 30 minutes before or after a meal, from day 1 continuing to day 10. The investigational drug and placebo were supplied by Dr. Willmar Schwabe GmbH & Co. (Karlsruhe, Germany). The investigational medication is a preparation of the roots of P sidoides, extraction solution: ethanol 11% (1:8-10) (wt/wt). The placebo was matched for color, smell, taste, and viscosity. Paracetamol (acetaminophen) tablets were allowed for all patients for fever greater than 39°C.

Primary endpoint. Severity of cold symptoms was evaluated using the Cold Intensity Score (CIS), a validated scale derived from the sum of scores for 10 cold-related symptoms (nasal drainage, sore throat, nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, and fever) on a scale of 0 to 4, where 0=not present and 4=very severe, to a maximum of 40 points. At baseline, the mean total CIS was comparable in both treatment and placebo groups (17.8±4.0 vs 16.9±3.4). From baseline to day 5, the mean total CIS decreased by 10.4±3.0 in the treatment group vs 5.6±4.3 in the placebo group (P<.0001).

Secondary endpoints. The number of patients achieving clinical cure (defined by CIS ≤1) by day 10 was significantly higher in the treatment group (78.8% vs 31.4%, P<.0001). The mean duration of days absent from work was significantly lower in the treatment group (6.9±1.8 vs 8.2±2.1, P<.0003), as was number of days with less than 100% usual activity level (7.1±1.5 vs 8.7±1.3, P<.0001). Data for both the primary and secondary endpoints were evaluated according to an intention-to-treat analysis. Both the intervention and placebo sides each had 4 patients that became ineligible after initial randomization. No patients were lost to follow-up.

Safety and tolerability. Patients in the low-dose arm experienced 3 nonserious adverse events, and 1 experienced mild epistaxis. Two additional patients (1 in the treatment and 1 in the placebo group) experienced moderate to severe tracheitis, not attributable to the study medication. Tolerability was rated slightly better in the treatment than placebo group on day 5. Forty-nine of 52 patients (94%) in the treatment group rated the preparation as good or very good tolerability vs 42 of 51 patients (82%) in the placebo group.

WHAT’S NEW?: A first

This is the first study that demonstrates the efficacy and safety of P sidoides in the treatment of the common cold. More importantly, this degree of improvement in cold symptoms is dramatically better than other common OTC treatments, including vitamin C, echinacea, and zinc preparations.

CAVEATS: How is this different from other cold remedies?

Patients are already spending a lot on cold remedies; this study suggests money would be better spent on having a ready supply of Pelargonium in the medicine cabinet, and it appears to be safe.

Other initially promising complementary and alternative therapies, such as zinc, echinacea, and vitamin C, have not been shown to be effective with more vigorous evaluation. We recognize that this is only 1 clinical trial, and the results may not be replicated in future trials. However, we are impressed by the effect size—twice the size as that seen for placebo, with a reduction in half of total cold symptom severity over 5 days and a reduction of missed time from work by more than a full day on average over placebo.

In vitro studies suggest a physiologic mechanism that is consistent with the study outcomes.

Similar findings are reported for symptom reduction in acute bronchitis.

Safety

There were no significant adverse events in this study, which is consistent with the findings of the studies of acute bronchitis.^12-14P sidoides has been widely used in Germany since the 1980s, with an annual sale value in 2002 of $55 million or 4.1 million packages.

The Uppsala Monitoring Centre, in conjunction with the World Health Organization international pharmacovigilance program, received 34 case reports between 2002 and 2006 of allergic reactions to ethanolic herbal extract of Pelargonium root, 2 of which involved life-threatening circulatory collapse requiring emergency medical attention. Given the extremely rare occurrence of these events we believe the minimal risk is acceptable. The others involved rash and pruritus.

Also of note: contact dermatitis to Pelargonium houseplants has been reported. As a result, product information will be added to product packaging, warning of common reactions of gastrointestinal complaints (gastric pain, heartburn, nausea, and diarrhea) as well as the potential for serious allergic reaction. In addition, since some of the active compounds are plant coumarins, there is a theoretical risk of interaction with warfarin and aspirin but no serious bleeding events have been reported.¹⁶

It is also recommended that individuals with renal or hepatic disease or women who are pregnant or breastfeeding avoid use of this preparation, as safety studies have not been performed.

Other study design issues

A few other issues struck us as important when assessing the validity of this study. For example, 1 of the authors appears to be an employee of the pharmaceutical company that manufactures the preparation, raising the conflict of interest issue.

We were also curious about why the results of the high-dose arm were not reported in this manuscript. Could there have been a higher rate of adverse events in the high-dose arm? Knowing how many patients were ineligible or excluded, and the efficacy or safety in the high-dose arm would give us more confidence in the findings, but we decided that these were not necessarily fatal flaws.

Bottom line

Despite the above caveats, this was a well-designed randomized controlled trial that suggests that P sidoides is impressively efficacious in decreasing the duration and severity of the common cold. In the final analysis, we think that these findings justify recommending this to our patients.

CHALLENGES TO IMPLEMENTATION: 2-day window

The medication was started within 48 hours of the onset of symptoms. We generally see patients seeking treatment for the common cold well after the first 2 days. The efficacy of Pelargonium is no doubt less when started later in the course of the illness. Colds resolve spontaneously, so to get the benefit of this treatment, it likely must be started early.

Our conclusion is that patients could be advised to purchase the medication to have on hand at home at the start of the cold season.

Availability of the drug

P sidoides is available in the US under the brand name Umcka Coldcare.

The preparation used in the study is marketed in Europe by ISO-Arzneimittel¹⁷ under the name Umckaloabo, which is a combination of the Zulu words for lung symptoms and breast pain.¹⁸

Our Internet search on the term “Pelargonium sidoides” failed to yield a distributor of the German preparation used in the study that would be available in the United States. However, a different manufacturer, Nature’s Way, distributes a number of similar preparations containing extract of the root of P sidoides under the name Umcka Coldcare. Umcka Cold-care appears to be readily available for purchase, both on-line and through local health food stores, for less than $20 per 4-oz (120-mL) bottle. A different retailer, African Red Tea, offers syrup, 1:10 ethanolic extract for $29.95 for 100-mL bottle.¹⁹ Like the German preparation, these formulations are delivered by dropper.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 39-year-old, otherwise healthy woman presents to your clinic with a sore throat, nasal congestion, and dry cough she’s had since yesterday. She wants an antibiotic, but your evaluation reveals an uncomplicated viral upper respiratory infection—a common cold. You would like to provide her with an alternative treatment, but you are aware of the lack of evidence for clear benefit of zinc lozenges, echinacea, and vitamin C. Is there any other medication that might benefit this patient?

Yes. Pelargonium sidoides, a species of South African geranium used for centuries in Zulu medicine,² shows promise as an herbal remedy for respiratory infections. Two randomized trials show that extracts of P sidoides improve symptoms of acute bronchitis which, like the common cold, is usually caused by a virus.^3-5

There is a plausible biological mechanism of action. In vitro studies show that Pelargonium extract induces the interferon system and up-regulates cytokines important in protecting host cells from viral infection.⁶

BACKGROUND: $17 billion dollar cold

Our patients want more relief from cold symptoms and are clearly willing to pay for it. Americans spend approximately $2.9 billion annually on over-the-counter (OTC) cold preparations and $1.1 billion on unnecessary antibiotics.⁷ The term “common cold” refers to a collection of symptoms, including sore throat, rhinorrhea, nasal congestion, cough, low-grade fever, and malaise, usually self-limited and lasting 10 to 14 days, caused by a number of viruses, most commonly by a rhinovirus.⁸ According to the 2005 National Ambulatory Medical Care Survey, the common cold is the third most common diagnosis in physicians’ offices behind only hypertension and well-infant/child visits.⁹ A 2001 US telephone survey determined that approximately 500 million episodes of non-influenza viral infection occur annually, resulting in direct costs of $17 billion for physician services and medications and approximately 200 million missed days of work.⁷

CLINICAL CONTEXT: Evidence proves most cold remedies don’t work

Although colds are common and result in annoying symptoms and missed work, much of the money spent on remedies is wasted. A truly effective treatment would be valuable to our patients.

Despite brisk sales, evidence for the efficacy of various cold remedies is inconclusive and contradictory. We found 6 Cochrane reviews of cold treatments, including antitussives, antihistamines, decongestants, vitamin C, echinacea, and zinc lozenges. With the exception of pseudoephedrine for nasal symptoms, the evidence that any product improves symptoms or decreases the duration of the cold is not encouraging.

Cough medications. The 2004 Cochrane Review of OTC medications for cough¹⁰ found no consistent evidence that any of them work. Codeine was no more effective than placebo for reducing cough symptoms. Three efficacy studies of dextromethorphan for cough showed either no difference or small but possibly clinically insignificant improvement in cough over placebo. One study of guaifenesin showed benefit over placebo in reducing cough frequency; another one showed no benefit over placebo.

Vitamin C, echinacea. Three Cochrane reviews found no conclusive evidence of benefit over placebo for either vitamin C¹¹ or echinacea¹² in treating the common cold.

Zinc. A new panel has been convened by the Cochrane group to reassess the effectiveness of zinc, but a 1999 Cochrane review¹³ found no benefit for zinc over placebo.

Antihistamines are not effective for relieving cold symptoms.¹⁴

Pseudoephedrine is the only medication with good-quality evidence for effectiveness, but only for reducing nasal symptoms.¹⁵ The authors concluded that patients may be encouraged to continue pseudoephedrine for up to 5 days if found to be effective with the first dose. Nasal congestion and discharge, however, are only 2 of the many irritating symptoms of a cold.

You can be a “REALITY CHECKER”

Bernard Ewigman, MD, MSPH

If you are in full-time clinical practice, a medical director of a practice, or otherwise directly involved in decision-making about adopting new practices, join our team of “reality checkers.”

Just email me at be.editor@gmail.com

STUDY SUMMARY: Duration and severity of symptoms are reduced

This was a multicenter, prospective, double-blind, placebo-controlled randomized trial to evaluate the effectiveness of a liquid herbal preparation from the roots of Pelargonium sidoides for decreasing the duration and severity of symptoms of the common cold.

Patient characteristics. Patients were recruited from 8 outpatient departments in Ukraine between December 2003 and May 2004. Two hundred and seven (207) patients were eligible. The number of ineligible and excluded patients was not stated. These 207 patients were randomized into 1 of 4 groups:

• 52 received 30 drops 3 times daily vs 51 patients who received placebo
• 52 patients received 60 drops 3 times daily vs 52 patients who received a higher-dose placebo.

The report gives the outcomes of the low-dose arm only. Two-thirds of the participants were women; all were Caucasian. Patients in the treatment and placebo groups were similar in terms of recurrent disease, prior use of medication for the common cold, smoking, and alcohol and caffeine consumption. All had a negative Group A beta-hemolytic strep test.

Inclusion criteria. Patients included men and women 18 to 55 years of age; able to provide written informed consent; with 2 major cold symptoms (nasal discharge, sore throat) and at least 1 minor cold symptom (nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, or fever) or presence of 1 major cold symptom and at least 3 minor cold symptoms; duration of symptoms 24 to 48 hours.

Exclusion criteria were any acute ear, nose, throat and respiratory tract disease other than the common cold; positive rapid strep test; 6 or more episodes of recurrent tonsillitis, sinusitis, or otitis within the past 12 months or any chronic ear, nose, throat or respiratory tract disease; treatment with antibiotics, glucocorticoids, or antihistamine drugs during the 4 weeks prior to enrollment in the trial; treatment with cold medications that might impair the trial results (eg, decongestants, local anesthetics); and use of cough or pain relief medications, or any other treatment for the common cold within 7 days prior to enrollment in the trial.

Treatment regimen. Patients were assigned to take 30 drops of either the study herbal preparation or 30 drops of placebo 3 times daily, at least 30 minutes before or after a meal, from day 1 continuing to day 10. The investigational drug and placebo were supplied by Dr. Willmar Schwabe GmbH & Co. (Karlsruhe, Germany). The investigational medication is a preparation of the roots of P sidoides, extraction solution: ethanol 11% (1:8-10) (wt/wt). The placebo was matched for color, smell, taste, and viscosity. Paracetamol (acetaminophen) tablets were allowed for all patients for fever greater than 39°C.

Primary endpoint. Severity of cold symptoms was evaluated using the Cold Intensity Score (CIS), a validated scale derived from the sum of scores for 10 cold-related symptoms (nasal drainage, sore throat, nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, and fever) on a scale of 0 to 4, where 0=not present and 4=very severe, to a maximum of 40 points. At baseline, the mean total CIS was comparable in both treatment and placebo groups (17.8±4.0 vs 16.9±3.4). From baseline to day 5, the mean total CIS decreased by 10.4±3.0 in the treatment group vs 5.6±4.3 in the placebo group (P<.0001).

Secondary endpoints. The number of patients achieving clinical cure (defined by CIS ≤1) by day 10 was significantly higher in the treatment group (78.8% vs 31.4%, P<.0001). The mean duration of days absent from work was significantly lower in the treatment group (6.9±1.8 vs 8.2±2.1, P<.0003), as was number of days with less than 100% usual activity level (7.1±1.5 vs 8.7±1.3, P<.0001). Data for both the primary and secondary endpoints were evaluated according to an intention-to-treat analysis. Both the intervention and placebo sides each had 4 patients that became ineligible after initial randomization. No patients were lost to follow-up.

Safety and tolerability. Patients in the low-dose arm experienced 3 nonserious adverse events, and 1 experienced mild epistaxis. Two additional patients (1 in the treatment and 1 in the placebo group) experienced moderate to severe tracheitis, not attributable to the study medication. Tolerability was rated slightly better in the treatment than placebo group on day 5. Forty-nine of 52 patients (94%) in the treatment group rated the preparation as good or very good tolerability vs 42 of 51 patients (82%) in the placebo group.

WHAT’S NEW?: A first

This is the first study that demonstrates the efficacy and safety of P sidoides in the treatment of the common cold. More importantly, this degree of improvement in cold symptoms is dramatically better than other common OTC treatments, including vitamin C, echinacea, and zinc preparations.

CAVEATS: How is this different from other cold remedies?

Patients are already spending a lot on cold remedies; this study suggests money would be better spent on having a ready supply of Pelargonium in the medicine cabinet, and it appears to be safe.

Other initially promising complementary and alternative therapies, such as zinc, echinacea, and vitamin C, have not been shown to be effective with more vigorous evaluation. We recognize that this is only 1 clinical trial, and the results may not be replicated in future trials. However, we are impressed by the effect size—twice the size as that seen for placebo, with a reduction in half of total cold symptom severity over 5 days and a reduction of missed time from work by more than a full day on average over placebo.

In vitro studies suggest a physiologic mechanism that is consistent with the study outcomes.

Similar findings are reported for symptom reduction in acute bronchitis.

Safety

There were no significant adverse events in this study, which is consistent with the findings of the studies of acute bronchitis.^12-14P sidoides has been widely used in Germany since the 1980s, with an annual sale value in 2002 of $55 million or 4.1 million packages.

The Uppsala Monitoring Centre, in conjunction with the World Health Organization international pharmacovigilance program, received 34 case reports between 2002 and 2006 of allergic reactions to ethanolic herbal extract of Pelargonium root, 2 of which involved life-threatening circulatory collapse requiring emergency medical attention. Given the extremely rare occurrence of these events we believe the minimal risk is acceptable. The others involved rash and pruritus.

Also of note: contact dermatitis to Pelargonium houseplants has been reported. As a result, product information will be added to product packaging, warning of common reactions of gastrointestinal complaints (gastric pain, heartburn, nausea, and diarrhea) as well as the potential for serious allergic reaction. In addition, since some of the active compounds are plant coumarins, there is a theoretical risk of interaction with warfarin and aspirin but no serious bleeding events have been reported.¹⁶

It is also recommended that individuals with renal or hepatic disease or women who are pregnant or breastfeeding avoid use of this preparation, as safety studies have not been performed.

Other study design issues

A few other issues struck us as important when assessing the validity of this study. For example, 1 of the authors appears to be an employee of the pharmaceutical company that manufactures the preparation, raising the conflict of interest issue.

We were also curious about why the results of the high-dose arm were not reported in this manuscript. Could there have been a higher rate of adverse events in the high-dose arm? Knowing how many patients were ineligible or excluded, and the efficacy or safety in the high-dose arm would give us more confidence in the findings, but we decided that these were not necessarily fatal flaws.

Bottom line

Despite the above caveats, this was a well-designed randomized controlled trial that suggests that P sidoides is impressively efficacious in decreasing the duration and severity of the common cold. In the final analysis, we think that these findings justify recommending this to our patients.

CHALLENGES TO IMPLEMENTATION: 2-day window

The medication was started within 48 hours of the onset of symptoms. We generally see patients seeking treatment for the common cold well after the first 2 days. The efficacy of Pelargonium is no doubt less when started later in the course of the illness. Colds resolve spontaneously, so to get the benefit of this treatment, it likely must be started early.

Our conclusion is that patients could be advised to purchase the medication to have on hand at home at the start of the cold season.

Availability of the drug

P sidoides is available in the US under the brand name Umcka Coldcare.

The preparation used in the study is marketed in Europe by ISO-Arzneimittel¹⁷ under the name Umckaloabo, which is a combination of the Zulu words for lung symptoms and breast pain.¹⁸

Our Internet search on the term “Pelargonium sidoides” failed to yield a distributor of the German preparation used in the study that would be available in the United States. However, a different manufacturer, Nature’s Way, distributes a number of similar preparations containing extract of the root of P sidoides under the name Umcka Coldcare. Umcka Cold-care appears to be readily available for purchase, both on-line and through local health food stores, for less than $20 per 4-oz (120-mL) bottle. A different retailer, African Red Tea, offers syrup, 1:10 ethanolic extract for $29.95 for 100-mL bottle.¹⁹ Like the German preparation, these formulations are delivered by dropper.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 39-year-old, otherwise healthy woman presents to your clinic with a sore throat, nasal congestion, and dry cough she’s had since yesterday. She wants an antibiotic, but your evaluation reveals an uncomplicated viral upper respiratory infection—a common cold. You would like to provide her with an alternative treatment, but you are aware of the lack of evidence for clear benefit of zinc lozenges, echinacea, and vitamin C. Is there any other medication that might benefit this patient?

Yes. Pelargonium sidoides, a species of South African geranium used for centuries in Zulu medicine,² shows promise as an herbal remedy for respiratory infections. Two randomized trials show that extracts of P sidoides improve symptoms of acute bronchitis which, like the common cold, is usually caused by a virus.^3-5

There is a plausible biological mechanism of action. In vitro studies show that Pelargonium extract induces the interferon system and up-regulates cytokines important in protecting host cells from viral infection.⁶

BACKGROUND: $17 billion dollar cold

Our patients want more relief from cold symptoms and are clearly willing to pay for it. Americans spend approximately $2.9 billion annually on over-the-counter (OTC) cold preparations and $1.1 billion on unnecessary antibiotics.⁷ The term “common cold” refers to a collection of symptoms, including sore throat, rhinorrhea, nasal congestion, cough, low-grade fever, and malaise, usually self-limited and lasting 10 to 14 days, caused by a number of viruses, most commonly by a rhinovirus.⁸ According to the 2005 National Ambulatory Medical Care Survey, the common cold is the third most common diagnosis in physicians’ offices behind only hypertension and well-infant/child visits.⁹ A 2001 US telephone survey determined that approximately 500 million episodes of non-influenza viral infection occur annually, resulting in direct costs of $17 billion for physician services and medications and approximately 200 million missed days of work.⁷

CLINICAL CONTEXT: Evidence proves most cold remedies don’t work

Although colds are common and result in annoying symptoms and missed work, much of the money spent on remedies is wasted. A truly effective treatment would be valuable to our patients.

Despite brisk sales, evidence for the efficacy of various cold remedies is inconclusive and contradictory. We found 6 Cochrane reviews of cold treatments, including antitussives, antihistamines, decongestants, vitamin C, echinacea, and zinc lozenges. With the exception of pseudoephedrine for nasal symptoms, the evidence that any product improves symptoms or decreases the duration of the cold is not encouraging.

Cough medications. The 2004 Cochrane Review of OTC medications for cough¹⁰ found no consistent evidence that any of them work. Codeine was no more effective than placebo for reducing cough symptoms. Three efficacy studies of dextromethorphan for cough showed either no difference or small but possibly clinically insignificant improvement in cough over placebo. One study of guaifenesin showed benefit over placebo in reducing cough frequency; another one showed no benefit over placebo.

Vitamin C, echinacea. Three Cochrane reviews found no conclusive evidence of benefit over placebo for either vitamin C¹¹ or echinacea¹² in treating the common cold.

Zinc. A new panel has been convened by the Cochrane group to reassess the effectiveness of zinc, but a 1999 Cochrane review¹³ found no benefit for zinc over placebo.

Antihistamines are not effective for relieving cold symptoms.¹⁴

Pseudoephedrine is the only medication with good-quality evidence for effectiveness, but only for reducing nasal symptoms.¹⁵ The authors concluded that patients may be encouraged to continue pseudoephedrine for up to 5 days if found to be effective with the first dose. Nasal congestion and discharge, however, are only 2 of the many irritating symptoms of a cold.

You can be a “REALITY CHECKER”

Bernard Ewigman, MD, MSPH

If you are in full-time clinical practice, a medical director of a practice, or otherwise directly involved in decision-making about adopting new practices, join our team of “reality checkers.”

Just email me at be.editor@gmail.com

STUDY SUMMARY: Duration and severity of symptoms are reduced

This was a multicenter, prospective, double-blind, placebo-controlled randomized trial to evaluate the effectiveness of a liquid herbal preparation from the roots of Pelargonium sidoides for decreasing the duration and severity of symptoms of the common cold.

Patient characteristics. Patients were recruited from 8 outpatient departments in Ukraine between December 2003 and May 2004. Two hundred and seven (207) patients were eligible. The number of ineligible and excluded patients was not stated. These 207 patients were randomized into 1 of 4 groups:

• 52 received 30 drops 3 times daily vs 51 patients who received placebo
• 52 patients received 60 drops 3 times daily vs 52 patients who received a higher-dose placebo.

The report gives the outcomes of the low-dose arm only. Two-thirds of the participants were women; all were Caucasian. Patients in the treatment and placebo groups were similar in terms of recurrent disease, prior use of medication for the common cold, smoking, and alcohol and caffeine consumption. All had a negative Group A beta-hemolytic strep test.

Inclusion criteria. Patients included men and women 18 to 55 years of age; able to provide written informed consent; with 2 major cold symptoms (nasal discharge, sore throat) and at least 1 minor cold symptom (nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, or fever) or presence of 1 major cold symptom and at least 3 minor cold symptoms; duration of symptoms 24 to 48 hours.

Exclusion criteria were any acute ear, nose, throat and respiratory tract disease other than the common cold; positive rapid strep test; 6 or more episodes of recurrent tonsillitis, sinusitis, or otitis within the past 12 months or any chronic ear, nose, throat or respiratory tract disease; treatment with antibiotics, glucocorticoids, or antihistamine drugs during the 4 weeks prior to enrollment in the trial; treatment with cold medications that might impair the trial results (eg, decongestants, local anesthetics); and use of cough or pain relief medications, or any other treatment for the common cold within 7 days prior to enrollment in the trial.

Treatment regimen. Patients were assigned to take 30 drops of either the study herbal preparation or 30 drops of placebo 3 times daily, at least 30 minutes before or after a meal, from day 1 continuing to day 10. The investigational drug and placebo were supplied by Dr. Willmar Schwabe GmbH & Co. (Karlsruhe, Germany). The investigational medication is a preparation of the roots of P sidoides, extraction solution: ethanol 11% (1:8-10) (wt/wt). The placebo was matched for color, smell, taste, and viscosity. Paracetamol (acetaminophen) tablets were allowed for all patients for fever greater than 39°C.

Primary endpoint. Severity of cold symptoms was evaluated using the Cold Intensity Score (CIS), a validated scale derived from the sum of scores for 10 cold-related symptoms (nasal drainage, sore throat, nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, and fever) on a scale of 0 to 4, where 0=not present and 4=very severe, to a maximum of 40 points. At baseline, the mean total CIS was comparable in both treatment and placebo groups (17.8±4.0 vs 16.9±3.4). From baseline to day 5, the mean total CIS decreased by 10.4±3.0 in the treatment group vs 5.6±4.3 in the placebo group (P<.0001).

Secondary endpoints. The number of patients achieving clinical cure (defined by CIS ≤1) by day 10 was significantly higher in the treatment group (78.8% vs 31.4%, P<.0001). The mean duration of days absent from work was significantly lower in the treatment group (6.9±1.8 vs 8.2±2.1, P<.0003), as was number of days with less than 100% usual activity level (7.1±1.5 vs 8.7±1.3, P<.0001). Data for both the primary and secondary endpoints were evaluated according to an intention-to-treat analysis. Both the intervention and placebo sides each had 4 patients that became ineligible after initial randomization. No patients were lost to follow-up.

Safety and tolerability. Patients in the low-dose arm experienced 3 nonserious adverse events, and 1 experienced mild epistaxis. Two additional patients (1 in the treatment and 1 in the placebo group) experienced moderate to severe tracheitis, not attributable to the study medication. Tolerability was rated slightly better in the treatment than placebo group on day 5. Forty-nine of 52 patients (94%) in the treatment group rated the preparation as good or very good tolerability vs 42 of 51 patients (82%) in the placebo group.

WHAT’S NEW?: A first

This is the first study that demonstrates the efficacy and safety of P sidoides in the treatment of the common cold. More importantly, this degree of improvement in cold symptoms is dramatically better than other common OTC treatments, including vitamin C, echinacea, and zinc preparations.

CAVEATS: How is this different from other cold remedies?

Patients are already spending a lot on cold remedies; this study suggests money would be better spent on having a ready supply of Pelargonium in the medicine cabinet, and it appears to be safe.

Other initially promising complementary and alternative therapies, such as zinc, echinacea, and vitamin C, have not been shown to be effective with more vigorous evaluation. We recognize that this is only 1 clinical trial, and the results may not be replicated in future trials. However, we are impressed by the effect size—twice the size as that seen for placebo, with a reduction in half of total cold symptom severity over 5 days and a reduction of missed time from work by more than a full day on average over placebo.

In vitro studies suggest a physiologic mechanism that is consistent with the study outcomes.

Similar findings are reported for symptom reduction in acute bronchitis.

Safety

There were no significant adverse events in this study, which is consistent with the findings of the studies of acute bronchitis.^12-14P sidoides has been widely used in Germany since the 1980s, with an annual sale value in 2002 of $55 million or 4.1 million packages.

The Uppsala Monitoring Centre, in conjunction with the World Health Organization international pharmacovigilance program, received 34 case reports between 2002 and 2006 of allergic reactions to ethanolic herbal extract of Pelargonium root, 2 of which involved life-threatening circulatory collapse requiring emergency medical attention. Given the extremely rare occurrence of these events we believe the minimal risk is acceptable. The others involved rash and pruritus.

Also of note: contact dermatitis to Pelargonium houseplants has been reported. As a result, product information will be added to product packaging, warning of common reactions of gastrointestinal complaints (gastric pain, heartburn, nausea, and diarrhea) as well as the potential for serious allergic reaction. In addition, since some of the active compounds are plant coumarins, there is a theoretical risk of interaction with warfarin and aspirin but no serious bleeding events have been reported.¹⁶

It is also recommended that individuals with renal or hepatic disease or women who are pregnant or breastfeeding avoid use of this preparation, as safety studies have not been performed.

Other study design issues

A few other issues struck us as important when assessing the validity of this study. For example, 1 of the authors appears to be an employee of the pharmaceutical company that manufactures the preparation, raising the conflict of interest issue.

We were also curious about why the results of the high-dose arm were not reported in this manuscript. Could there have been a higher rate of adverse events in the high-dose arm? Knowing how many patients were ineligible or excluded, and the efficacy or safety in the high-dose arm would give us more confidence in the findings, but we decided that these were not necessarily fatal flaws.

Bottom line

Despite the above caveats, this was a well-designed randomized controlled trial that suggests that P sidoides is impressively efficacious in decreasing the duration and severity of the common cold. In the final analysis, we think that these findings justify recommending this to our patients.

CHALLENGES TO IMPLEMENTATION: 2-day window

The medication was started within 48 hours of the onset of symptoms. We generally see patients seeking treatment for the common cold well after the first 2 days. The efficacy of Pelargonium is no doubt less when started later in the course of the illness. Colds resolve spontaneously, so to get the benefit of this treatment, it likely must be started early.

Our conclusion is that patients could be advised to purchase the medication to have on hand at home at the start of the cold season.

Availability of the drug

P sidoides is available in the US under the brand name Umcka Coldcare.

The preparation used in the study is marketed in Europe by ISO-Arzneimittel¹⁷ under the name Umckaloabo, which is a combination of the Zulu words for lung symptoms and breast pain.¹⁸

Our Internet search on the term “Pelargonium sidoides” failed to yield a distributor of the German preparation used in the study that would be available in the United States. However, a different manufacturer, Nature’s Way, distributes a number of similar preparations containing extract of the root of P sidoides under the name Umcka Coldcare. Umcka Cold-care appears to be readily available for purchase, both on-line and through local health food stores, for less than $20 per 4-oz (120-mL) bottle. A different retailer, African Red Tea, offers syrup, 1:10 ethanolic extract for $29.95 for 100-mL bottle.¹⁹ Like the German preparation, these formulations are delivered by dropper.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

The methacholine challenge test isused in several situations:

If the diagnosis of asthma is in question, eg, if the patient has symptoms that suggest asthma (either typical symptoms such as coughing, wheezing, and dyspnea or atypical symptoms) but normal results on regular spirometric testing and no response to a bronchodilator. Because the test has a high negative predictive value, it is more useful in ruling out asthma (if the result is negative) than in ruling it in (if the result is positive).^1,2 A negative methacholine challenge test nearly rules out asthma; however, a positive test result needs to be interpreted cautiously if the patient is not experiencing symptoms.

In establishing a diagnosis of occupational asthma. For patients with remitting and relapsing symptoms suggestive of asthma associated with a particular work environment, a detailed history, physical examination, and methacholine challenge test can establish the diagnosis. Specific bronchial challenge testing with the suspected offending agent is possible, although this is more frequently used in research and in situations with significant legal or financial implications for the patient, such as workers’ compensation cases.³

Possibly, in managing asthma. In several clinical trials,^4,5 outcomes were better when asthma management decisions were based on airway hyper responsiveness combined with conventional factors (symptoms and lung function) than with management based on conventional factors alone. These findings suggest that asthma management based on serial measurement of airway hyperresponsiveness may be useful in optimizing outcomes of care; however, adjustment in treatment according to response to serial methacholine challenge tests is currently not recommended for routine management of asthma.

In clinical research.

OBSTRUCTION CAN BE IMPROVED OR PROVOKED

Asthma is a chronic inflammatory disorder of the airways associated with characteristic clinical symptoms of wheezing, chest tightness, breathlessness, and cough. These symptoms may be associated with airflow limitation that is at least partially reversible, either spontaneously or with treatment.

Spirometry can confirm the diagnosis of asthma if lung function improves after a bronchodilator is given, as reflected by an increase in forced expiratory volume in 1 second (FEV₁) of more than 12% and more than 0.2 L.^6,7

Conversely, during bronchoprovocation testing, airflow obstruction is provoked by a stimulus known to elicit airway narrowing, such as inhaled methacholine. Bronchial hyperresponsiveness can reliably distinguish patients with asthma from those without asthma.

HOW THE TEST IS DONE

During the test, the patient inhales methacholine aerosols in increasing concentrations; various protocols can be used. Spirometry is performed before and after each dose, and the results are reported as a percent decrease in FEV₁ from baseline for each step of the protocol.

A positive reaction is a 20% fall in FEV₁, and the provocative concentration that causes a positive reaction (the PC₂₀) is used to indicate the level of airway hyperresponsiveness. If the FEV₁ does not fall by at least 20% with the highest concentration of methacholine, the testis interpreted as negative and the PC₂₀ is reported as “more than 16 mg/mL” or “more than 25 mg/mL,” depending on the highest dose given.

The maximum dose of methacholine varies among pulmonary function testing laboratories and asthma specialists; final doses of 16, 25, and 32 mg/mL are commonly used. Studies have defined a range of 8 to 16 mg/mL as an optimal cutoff point to separate patients with asthma from those without asthma.^2,6,7

The response to methacholine can also be expressed in terms of specific airway conductance;however, this is more complicated and requires body plethysmography.

Other stimuli that can be used as bronchoprovocation challenges to diagnose asthma include inhaled histamine, exposure to cold air, or eucapneic hyperventilation.Compared with these alternative stimuli, methacholine is the most feasible as it does not require extensive equipment and is better tolerated than histamine.⁸

POTENTIAL COMPLICATIONS

Methacholine elicits airway narrowing in susceptible people and can cause severe bronchoconstriction, hyperinflation, or severe coughing. However, this procedure is generally well tolerated, and respiratory symptoms inpatients who react to methacholine typically reverse promptly in response to bronchodilators.

Nevertheless, the test should be performed in a pulmonary function laboratory or doctor’s office with available personnel trained to treat acute bronchospasm and to use resuscitation equipment if needed. Informed consent should be obtained and recorded in the medical record after a detailed explanation of the risks and benefits of this procedure and alternatives to it.

CONTRAINDICATIONS

Baseline obstruction. A ratio of FEV₁ to forced vital capacity less than 70% on baseline spirometry defines airway obstruction, and methacholine challenge for diagnostic purposes would not be indicated.

Furthermore, patients with low baseline lung function, who may not be able to compensate for a further decline in lung function due to methacholine-induced bronchospasm, are at increased risk of a serious respiratory reaction. For this reason, an FEV₁ less than 50% of predicted or less than 1.0 L is an absolute contraindication to methacholine challenge testing, and an FEV₁ less than 60% of predicted or less than 1.5 L must be evaluated on an individual basis.⁹

Myocardial infarction or stroke within the previous 3 months, uncontrolled hypertension, and aortic or cerebral aneurysm are absolute contraindications to this procedure, since induced bronchospasm may cause ventilation-perfusion mismatching resulting in arterial hypoxemia and compensatory changes in blood pressure, cardiac output, and heart rate. There is no increased risk of cardiac arrhythmia during methacholine challenge.¹⁰

Pregnancy is a relative contraindication to methacholine challenge testing; metha- choline is classified in pregnancy category C.

Inability to perform spirometry correctly is also a relative contraindication, and therefore this test is not recommended for preschool-age children.

SOME DRUGS SHOULD BE HELD

Other factors that can confound the results include smoking,¹⁶ respiratory infection, exercise, and consumption of caffeine (coffee, tea, chocolate, or cola drinks) on the day of the test. Airway responsiveness may worsen due to exposure to allergen or upper airway viral infections. Vigorous exercise could induce bronchoconstriction; therefore, performing other bronchial challenge procedures or exercise testing immediately before methacholine challenge may affect the results.^17,18

Bronchial hyperresponsiveness is seen in a variety of disorders other than asthma, such as smoking-induced chronic airflow limitation, congestive heart failure, sarcoidosis, cysticfibrosis, and bronchiectasis, as well as in siblings of asthmatics and in people with allergic rhinitis.¹⁹ In these situations, the methacholine test can be falsely positive, and one should interpret the results in the context of the clinical history.

The methacholine challenge test isused in several situations:

If the diagnosis of asthma is in question, eg, if the patient has symptoms that suggest asthma (either typical symptoms such as coughing, wheezing, and dyspnea or atypical symptoms) but normal results on regular spirometric testing and no response to a bronchodilator. Because the test has a high negative predictive value, it is more useful in ruling out asthma (if the result is negative) than in ruling it in (if the result is positive).^1,2 A negative methacholine challenge test nearly rules out asthma; however, a positive test result needs to be interpreted cautiously if the patient is not experiencing symptoms.

In establishing a diagnosis of occupational asthma. For patients with remitting and relapsing symptoms suggestive of asthma associated with a particular work environment, a detailed history, physical examination, and methacholine challenge test can establish the diagnosis. Specific bronchial challenge testing with the suspected offending agent is possible, although this is more frequently used in research and in situations with significant legal or financial implications for the patient, such as workers’ compensation cases.³

Possibly, in managing asthma. In several clinical trials,^4,5 outcomes were better when asthma management decisions were based on airway hyper responsiveness combined with conventional factors (symptoms and lung function) than with management based on conventional factors alone. These findings suggest that asthma management based on serial measurement of airway hyperresponsiveness may be useful in optimizing outcomes of care; however, adjustment in treatment according to response to serial methacholine challenge tests is currently not recommended for routine management of asthma.

In clinical research.

OBSTRUCTION CAN BE IMPROVED OR PROVOKED

Asthma is a chronic inflammatory disorder of the airways associated with characteristic clinical symptoms of wheezing, chest tightness, breathlessness, and cough. These symptoms may be associated with airflow limitation that is at least partially reversible, either spontaneously or with treatment.

Spirometry can confirm the diagnosis of asthma if lung function improves after a bronchodilator is given, as reflected by an increase in forced expiratory volume in 1 second (FEV₁) of more than 12% and more than 0.2 L.^6,7

Conversely, during bronchoprovocation testing, airflow obstruction is provoked by a stimulus known to elicit airway narrowing, such as inhaled methacholine. Bronchial hyperresponsiveness can reliably distinguish patients with asthma from those without asthma.

HOW THE TEST IS DONE

During the test, the patient inhales methacholine aerosols in increasing concentrations; various protocols can be used. Spirometry is performed before and after each dose, and the results are reported as a percent decrease in FEV₁ from baseline for each step of the protocol.

A positive reaction is a 20% fall in FEV₁, and the provocative concentration that causes a positive reaction (the PC₂₀) is used to indicate the level of airway hyperresponsiveness. If the FEV₁ does not fall by at least 20% with the highest concentration of methacholine, the testis interpreted as negative and the PC₂₀ is reported as “more than 16 mg/mL” or “more than 25 mg/mL,” depending on the highest dose given.

The maximum dose of methacholine varies among pulmonary function testing laboratories and asthma specialists; final doses of 16, 25, and 32 mg/mL are commonly used. Studies have defined a range of 8 to 16 mg/mL as an optimal cutoff point to separate patients with asthma from those without asthma.^2,6,7

The response to methacholine can also be expressed in terms of specific airway conductance;however, this is more complicated and requires body plethysmography.

Other stimuli that can be used as bronchoprovocation challenges to diagnose asthma include inhaled histamine, exposure to cold air, or eucapneic hyperventilation.Compared with these alternative stimuli, methacholine is the most feasible as it does not require extensive equipment and is better tolerated than histamine.⁸

POTENTIAL COMPLICATIONS

Methacholine elicits airway narrowing in susceptible people and can cause severe bronchoconstriction, hyperinflation, or severe coughing. However, this procedure is generally well tolerated, and respiratory symptoms inpatients who react to methacholine typically reverse promptly in response to bronchodilators.

Nevertheless, the test should be performed in a pulmonary function laboratory or doctor’s office with available personnel trained to treat acute bronchospasm and to use resuscitation equipment if needed. Informed consent should be obtained and recorded in the medical record after a detailed explanation of the risks and benefits of this procedure and alternatives to it.

CONTRAINDICATIONS

Baseline obstruction. A ratio of FEV₁ to forced vital capacity less than 70% on baseline spirometry defines airway obstruction, and methacholine challenge for diagnostic purposes would not be indicated.

Furthermore, patients with low baseline lung function, who may not be able to compensate for a further decline in lung function due to methacholine-induced bronchospasm, are at increased risk of a serious respiratory reaction. For this reason, an FEV₁ less than 50% of predicted or less than 1.0 L is an absolute contraindication to methacholine challenge testing, and an FEV₁ less than 60% of predicted or less than 1.5 L must be evaluated on an individual basis.⁹

Myocardial infarction or stroke within the previous 3 months, uncontrolled hypertension, and aortic or cerebral aneurysm are absolute contraindications to this procedure, since induced bronchospasm may cause ventilation-perfusion mismatching resulting in arterial hypoxemia and compensatory changes in blood pressure, cardiac output, and heart rate. There is no increased risk of cardiac arrhythmia during methacholine challenge.¹⁰

Pregnancy is a relative contraindication to methacholine challenge testing; metha- choline is classified in pregnancy category C.

Inability to perform spirometry correctly is also a relative contraindication, and therefore this test is not recommended for preschool-age children.

SOME DRUGS SHOULD BE HELD

Other factors that can confound the results include smoking,¹⁶ respiratory infection, exercise, and consumption of caffeine (coffee, tea, chocolate, or cola drinks) on the day of the test. Airway responsiveness may worsen due to exposure to allergen or upper airway viral infections. Vigorous exercise could induce bronchoconstriction; therefore, performing other bronchial challenge procedures or exercise testing immediately before methacholine challenge may affect the results.^17,18

Bronchial hyperresponsiveness is seen in a variety of disorders other than asthma, such as smoking-induced chronic airflow limitation, congestive heart failure, sarcoidosis, cysticfibrosis, and bronchiectasis, as well as in siblings of asthmatics and in people with allergic rhinitis.¹⁹ In these situations, the methacholine test can be falsely positive, and one should interpret the results in the context of the clinical history.

The methacholine challenge test isused in several situations:

If the diagnosis of asthma is in question, eg, if the patient has symptoms that suggest asthma (either typical symptoms such as coughing, wheezing, and dyspnea or atypical symptoms) but normal results on regular spirometric testing and no response to a bronchodilator. Because the test has a high negative predictive value, it is more useful in ruling out asthma (if the result is negative) than in ruling it in (if the result is positive).^1,2 A negative methacholine challenge test nearly rules out asthma; however, a positive test result needs to be interpreted cautiously if the patient is not experiencing symptoms.

In establishing a diagnosis of occupational asthma. For patients with remitting and relapsing symptoms suggestive of asthma associated with a particular work environment, a detailed history, physical examination, and methacholine challenge test can establish the diagnosis. Specific bronchial challenge testing with the suspected offending agent is possible, although this is more frequently used in research and in situations with significant legal or financial implications for the patient, such as workers’ compensation cases.³

Possibly, in managing asthma. In several clinical trials,^4,5 outcomes were better when asthma management decisions were based on airway hyper responsiveness combined with conventional factors (symptoms and lung function) than with management based on conventional factors alone. These findings suggest that asthma management based on serial measurement of airway hyperresponsiveness may be useful in optimizing outcomes of care; however, adjustment in treatment according to response to serial methacholine challenge tests is currently not recommended for routine management of asthma.

In clinical research.

OBSTRUCTION CAN BE IMPROVED OR PROVOKED

Asthma is a chronic inflammatory disorder of the airways associated with characteristic clinical symptoms of wheezing, chest tightness, breathlessness, and cough. These symptoms may be associated with airflow limitation that is at least partially reversible, either spontaneously or with treatment.

Spirometry can confirm the diagnosis of asthma if lung function improves after a bronchodilator is given, as reflected by an increase in forced expiratory volume in 1 second (FEV₁) of more than 12% and more than 0.2 L.^6,7

Conversely, during bronchoprovocation testing, airflow obstruction is provoked by a stimulus known to elicit airway narrowing, such as inhaled methacholine. Bronchial hyperresponsiveness can reliably distinguish patients with asthma from those without asthma.

HOW THE TEST IS DONE

During the test, the patient inhales methacholine aerosols in increasing concentrations; various protocols can be used. Spirometry is performed before and after each dose, and the results are reported as a percent decrease in FEV₁ from baseline for each step of the protocol.

A positive reaction is a 20% fall in FEV₁, and the provocative concentration that causes a positive reaction (the PC₂₀) is used to indicate the level of airway hyperresponsiveness. If the FEV₁ does not fall by at least 20% with the highest concentration of methacholine, the testis interpreted as negative and the PC₂₀ is reported as “more than 16 mg/mL” or “more than 25 mg/mL,” depending on the highest dose given.

The maximum dose of methacholine varies among pulmonary function testing laboratories and asthma specialists; final doses of 16, 25, and 32 mg/mL are commonly used. Studies have defined a range of 8 to 16 mg/mL as an optimal cutoff point to separate patients with asthma from those without asthma.^2,6,7

The response to methacholine can also be expressed in terms of specific airway conductance;however, this is more complicated and requires body plethysmography.

Other stimuli that can be used as bronchoprovocation challenges to diagnose asthma include inhaled histamine, exposure to cold air, or eucapneic hyperventilation.Compared with these alternative stimuli, methacholine is the most feasible as it does not require extensive equipment and is better tolerated than histamine.⁸

POTENTIAL COMPLICATIONS

Methacholine elicits airway narrowing in susceptible people and can cause severe bronchoconstriction, hyperinflation, or severe coughing. However, this procedure is generally well tolerated, and respiratory symptoms inpatients who react to methacholine typically reverse promptly in response to bronchodilators.

Nevertheless, the test should be performed in a pulmonary function laboratory or doctor’s office with available personnel trained to treat acute bronchospasm and to use resuscitation equipment if needed. Informed consent should be obtained and recorded in the medical record after a detailed explanation of the risks and benefits of this procedure and alternatives to it.

CONTRAINDICATIONS

Baseline obstruction. A ratio of FEV₁ to forced vital capacity less than 70% on baseline spirometry defines airway obstruction, and methacholine challenge for diagnostic purposes would not be indicated.

Furthermore, patients with low baseline lung function, who may not be able to compensate for a further decline in lung function due to methacholine-induced bronchospasm, are at increased risk of a serious respiratory reaction. For this reason, an FEV₁ less than 50% of predicted or less than 1.0 L is an absolute contraindication to methacholine challenge testing, and an FEV₁ less than 60% of predicted or less than 1.5 L must be evaluated on an individual basis.⁹

Myocardial infarction or stroke within the previous 3 months, uncontrolled hypertension, and aortic or cerebral aneurysm are absolute contraindications to this procedure, since induced bronchospasm may cause ventilation-perfusion mismatching resulting in arterial hypoxemia and compensatory changes in blood pressure, cardiac output, and heart rate. There is no increased risk of cardiac arrhythmia during methacholine challenge.¹⁰

Pregnancy is a relative contraindication to methacholine challenge testing; metha- choline is classified in pregnancy category C.

Inability to perform spirometry correctly is also a relative contraindication, and therefore this test is not recommended for preschool-age children.

SOME DRUGS SHOULD BE HELD

Other factors that can confound the results include smoking,¹⁶ respiratory infection, exercise, and consumption of caffeine (coffee, tea, chocolate, or cola drinks) on the day of the test. Airway responsiveness may worsen due to exposure to allergen or upper airway viral infections. Vigorous exercise could induce bronchoconstriction; therefore, performing other bronchial challenge procedures or exercise testing immediately before methacholine challenge may affect the results.^17,18

Bronchial hyperresponsiveness is seen in a variety of disorders other than asthma, such as smoking-induced chronic airflow limitation, congestive heart failure, sarcoidosis, cysticfibrosis, and bronchiectasis, as well as in siblings of asthmatics and in people with allergic rhinitis.¹⁹ In these situations, the methacholine test can be falsely positive, and one should interpret the results in the context of the clinical history.

Evidence summary

Little research has been performed on sulfonamide antibiotic and sulfonamide diuretic allergic cross-reactivity. What we do know is that there are 2 classes of sulfonamides—those with an aromatic amine (the antimicrobial sulfonamides) and those without (eg, the diuretics acetazolamide, furosemide, hydrochlorothiazide, and indapamide). Hypersensitivity reactions occur when the aromatic amine group is oxidized into hydroxylamine metabolites by the liver. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways, suggesting that allergic reactions that do occur in this group are not due to cross-reactivity in sulfa-allergic patients. But that point is far from settled by the research.

On one side, a large cohort study shows some cross-reactivity

A large retrospective cohort study using Britain’s General Practice Research Database identified 20,226 patients seen from 1987 through March 1999 who were prescribed a systemic sulfonamide antibiotic, and then at least 60 days later received a nonantibiotic sulfonamide (eg, thiazide diuretic, furosemide, oral hypoglycemic).¹ Researchers reviewed records to determine whether patients described as having an allergic reaction to a sulfonamide antibiotic were at increased risk of having a subsequent allergic reaction to a sulfonamide nonantibiotic.

Patients were identified as being allergic using both narrow definitions (anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) and broad ones. As only 18 patients out of the 20,226 patients were reported as having an allergic reaction using the narrow definition, analysis was based on the broad definition. Added to the broad category were asthma, eczema, and other “adverse” drug effects that were not specified by the author.

Using this broad definition, researchers identified allergies to sulfonamide antibiotics in 969 patients. Of this group, 96 patients (9.9%) had a subsequent reaction to a sulfonamide nonantibiotic, which included drugs from the loop and thiazide diuretic classes (including bumetanide, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, and torsemide). It was unclear if any patients taking a carbonic anhydrase inhibitor experienced an allergic reaction. For comparison purposes, of the 19,257 patients who were not identified as having an allergy to a sulfonamide antibiotic, again using the broad definition, 315 (1.6%), had a subsequent allergic reaction to a sulfonamide nonantibiotic, for an unadjusted odds ratio of 6.6 (95% confidence interval [CI], 5.2–8.4).

When the results were adjusted for age, sex, history of asthma, use of medications for asthma or corticosteroids, the adjusted odds ratio for individuals experiencing an allergy to a nonantibiotic sulfonamide in those persons with a history of allergy to a sulfonamide antibiotic was 2.8 (95 % CI, 2.1–3.7). Of note, the adjusted odds ratio for the occurrence of a penicillin allergy in a patient with a history of sulfonamide antibiotic allergy was significantly higher at 3.9 (95% CI, 3.5–4.3).

Some limitations of the study included uncertainty of cause and effect of prescribed medications and subsequent reactions, possible inconsistency of physician diagnosis and coding, and lack of precision in the diagnosis of allergic reactions. There is also the possibility of “suspicion bias,” where patients with a history of allergies may be more closely monitored for subsequent reactions than nonallergic patients.

On the other side, small studies reveal little risk of cross-reaction

Researchers involved in a retrospective study of 363 hospital charts examined 34 patients with a self-reported history of sulfa allergy who were subsequently given acetazolamide (a carbonic anhydrase inhibitor), furosemide (a loop diuretic), or both.² The nature of the self-reported sulfa allergic reaction was documented in 79% of the 34 patients. These reported reactions included urticarial rash, nonspecified rash, dyspnea, swelling, nausea or vomiting, throat swelling, red eyes, and bullae. Two patients who were given acetazolamide developed urticaria. No allergic reactions occurred for those patients given furosemide.

The researchers concluded that there was little clinical or pharmacological evidence to suggest that a self-reported sulfa allergy was likely to produce a life-threatening cross-reaction with acetazolamide or furosemide. Small numbers and the lack of a standard definition for an allergic reaction limited the strength of their conclusion.

A small single-blind study of 28 patients with a history of fixed drug eruption to sulfonamide antibiotics examined the usefulness of patch testing as an alternative to controlled oral challenge testing.³ Before patch testing, a sulfonamide antibiotic allergy was confirmed by each patient with an oral challenge of sulfamethoxazole, sulfadiazine, or sulfamethazole. Potential cross-reactivity to several nonantibiotic sulfonamides (including furosemide) was also investigated using controlled oral challenge testing of these agents. Every patient tolerated a subsequent oral challenge with furosemide.

Literature reviews limited by small numbers

Two literature reviews examined the small number of case series, case reports, and “other articles” and concluded little evidence supports the presence of cross-reactivity between sulfonamide antibiotics and non-sulfonamide antibiotics.^3,4 These reviews were limited by their search criteria and lack of explicit critical appraisal.

A literature review of Medline from 1966 to early 2004 revealed 21 case series, case reports, and “other articles” that evaluated the presence of cross-reactivity.³ When the authors of this literature reviewed drilled down to diuretics, they found 5 case reports for cross-reactivity to acetazolamide, 2 case reports for furosemide, 1 case series, and 2 case reports for indapamide (a thiazide diuretic). After reviewing the studies, the authors concluded that little evidence suggested a problem with cross-reactivity either with acetazolamide or furosemide and that there may be an association of cross-reactivity between sulfonamide antibiotics and indapamide. This study was limited by its small numbers and lack of explicit critical appraisal.

In another literature review—in which the main focus was cross-reactivity between sulfonamide antibiotics and celecoxib—the authors concluded that little evidence supported definitive cross-reactivity between sulfonamide antibiotics and diuretics.⁴ The limitations of this study were similar to those of the previous study.

Recommendations from others

The manufacturer insert for furosemide states, under the heading “General Precautions,” that “patients allergic to sulfonamides may also be allergic to furosemide.”⁵ A similar warning occurs for hydrochlorothiazide under the heading “Contraindications.”⁶

Evidence summary

Little research has been performed on sulfonamide antibiotic and sulfonamide diuretic allergic cross-reactivity. What we do know is that there are 2 classes of sulfonamides—those with an aromatic amine (the antimicrobial sulfonamides) and those without (eg, the diuretics acetazolamide, furosemide, hydrochlorothiazide, and indapamide). Hypersensitivity reactions occur when the aromatic amine group is oxidized into hydroxylamine metabolites by the liver. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways, suggesting that allergic reactions that do occur in this group are not due to cross-reactivity in sulfa-allergic patients. But that point is far from settled by the research.

On one side, a large cohort study shows some cross-reactivity

A large retrospective cohort study using Britain’s General Practice Research Database identified 20,226 patients seen from 1987 through March 1999 who were prescribed a systemic sulfonamide antibiotic, and then at least 60 days later received a nonantibiotic sulfonamide (eg, thiazide diuretic, furosemide, oral hypoglycemic).¹ Researchers reviewed records to determine whether patients described as having an allergic reaction to a sulfonamide antibiotic were at increased risk of having a subsequent allergic reaction to a sulfonamide nonantibiotic.

Patients were identified as being allergic using both narrow definitions (anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) and broad ones. As only 18 patients out of the 20,226 patients were reported as having an allergic reaction using the narrow definition, analysis was based on the broad definition. Added to the broad category were asthma, eczema, and other “adverse” drug effects that were not specified by the author.

Using this broad definition, researchers identified allergies to sulfonamide antibiotics in 969 patients. Of this group, 96 patients (9.9%) had a subsequent reaction to a sulfonamide nonantibiotic, which included drugs from the loop and thiazide diuretic classes (including bumetanide, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, and torsemide). It was unclear if any patients taking a carbonic anhydrase inhibitor experienced an allergic reaction. For comparison purposes, of the 19,257 patients who were not identified as having an allergy to a sulfonamide antibiotic, again using the broad definition, 315 (1.6%), had a subsequent allergic reaction to a sulfonamide nonantibiotic, for an unadjusted odds ratio of 6.6 (95% confidence interval [CI], 5.2–8.4).

When the results were adjusted for age, sex, history of asthma, use of medications for asthma or corticosteroids, the adjusted odds ratio for individuals experiencing an allergy to a nonantibiotic sulfonamide in those persons with a history of allergy to a sulfonamide antibiotic was 2.8 (95 % CI, 2.1–3.7). Of note, the adjusted odds ratio for the occurrence of a penicillin allergy in a patient with a history of sulfonamide antibiotic allergy was significantly higher at 3.9 (95% CI, 3.5–4.3).

Some limitations of the study included uncertainty of cause and effect of prescribed medications and subsequent reactions, possible inconsistency of physician diagnosis and coding, and lack of precision in the diagnosis of allergic reactions. There is also the possibility of “suspicion bias,” where patients with a history of allergies may be more closely monitored for subsequent reactions than nonallergic patients.

On the other side, small studies reveal little risk of cross-reaction

Researchers involved in a retrospective study of 363 hospital charts examined 34 patients with a self-reported history of sulfa allergy who were subsequently given acetazolamide (a carbonic anhydrase inhibitor), furosemide (a loop diuretic), or both.² The nature of the self-reported sulfa allergic reaction was documented in 79% of the 34 patients. These reported reactions included urticarial rash, nonspecified rash, dyspnea, swelling, nausea or vomiting, throat swelling, red eyes, and bullae. Two patients who were given acetazolamide developed urticaria. No allergic reactions occurred for those patients given furosemide.

The researchers concluded that there was little clinical or pharmacological evidence to suggest that a self-reported sulfa allergy was likely to produce a life-threatening cross-reaction with acetazolamide or furosemide. Small numbers and the lack of a standard definition for an allergic reaction limited the strength of their conclusion.

A small single-blind study of 28 patients with a history of fixed drug eruption to sulfonamide antibiotics examined the usefulness of patch testing as an alternative to controlled oral challenge testing.³ Before patch testing, a sulfonamide antibiotic allergy was confirmed by each patient with an oral challenge of sulfamethoxazole, sulfadiazine, or sulfamethazole. Potential cross-reactivity to several nonantibiotic sulfonamides (including furosemide) was also investigated using controlled oral challenge testing of these agents. Every patient tolerated a subsequent oral challenge with furosemide.

Literature reviews limited by small numbers

Two literature reviews examined the small number of case series, case reports, and “other articles” and concluded little evidence supports the presence of cross-reactivity between sulfonamide antibiotics and non-sulfonamide antibiotics.^3,4 These reviews were limited by their search criteria and lack of explicit critical appraisal.

A literature review of Medline from 1966 to early 2004 revealed 21 case series, case reports, and “other articles” that evaluated the presence of cross-reactivity.³ When the authors of this literature reviewed drilled down to diuretics, they found 5 case reports for cross-reactivity to acetazolamide, 2 case reports for furosemide, 1 case series, and 2 case reports for indapamide (a thiazide diuretic). After reviewing the studies, the authors concluded that little evidence suggested a problem with cross-reactivity either with acetazolamide or furosemide and that there may be an association of cross-reactivity between sulfonamide antibiotics and indapamide. This study was limited by its small numbers and lack of explicit critical appraisal.

In another literature review—in which the main focus was cross-reactivity between sulfonamide antibiotics and celecoxib—the authors concluded that little evidence supported definitive cross-reactivity between sulfonamide antibiotics and diuretics.⁴ The limitations of this study were similar to those of the previous study.

Recommendations from others

The manufacturer insert for furosemide states, under the heading “General Precautions,” that “patients allergic to sulfonamides may also be allergic to furosemide.”⁵ A similar warning occurs for hydrochlorothiazide under the heading “Contraindications.”⁶

Evidence summary

Little research has been performed on sulfonamide antibiotic and sulfonamide diuretic allergic cross-reactivity. What we do know is that there are 2 classes of sulfonamides—those with an aromatic amine (the antimicrobial sulfonamides) and those without (eg, the diuretics acetazolamide, furosemide, hydrochlorothiazide, and indapamide). Hypersensitivity reactions occur when the aromatic amine group is oxidized into hydroxylamine metabolites by the liver. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways, suggesting that allergic reactions that do occur in this group are not due to cross-reactivity in sulfa-allergic patients. But that point is far from settled by the research.

On one side, a large cohort study shows some cross-reactivity

A large retrospective cohort study using Britain’s General Practice Research Database identified 20,226 patients seen from 1987 through March 1999 who were prescribed a systemic sulfonamide antibiotic, and then at least 60 days later received a nonantibiotic sulfonamide (eg, thiazide diuretic, furosemide, oral hypoglycemic).¹ Researchers reviewed records to determine whether patients described as having an allergic reaction to a sulfonamide antibiotic were at increased risk of having a subsequent allergic reaction to a sulfonamide nonantibiotic.

Patients were identified as being allergic using both narrow definitions (anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) and broad ones. As only 18 patients out of the 20,226 patients were reported as having an allergic reaction using the narrow definition, analysis was based on the broad definition. Added to the broad category were asthma, eczema, and other “adverse” drug effects that were not specified by the author.

Using this broad definition, researchers identified allergies to sulfonamide antibiotics in 969 patients. Of this group, 96 patients (9.9%) had a subsequent reaction to a sulfonamide nonantibiotic, which included drugs from the loop and thiazide diuretic classes (including bumetanide, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, and torsemide). It was unclear if any patients taking a carbonic anhydrase inhibitor experienced an allergic reaction. For comparison purposes, of the 19,257 patients who were not identified as having an allergy to a sulfonamide antibiotic, again using the broad definition, 315 (1.6%), had a subsequent allergic reaction to a sulfonamide nonantibiotic, for an unadjusted odds ratio of 6.6 (95% confidence interval [CI], 5.2–8.4).

When the results were adjusted for age, sex, history of asthma, use of medications for asthma or corticosteroids, the adjusted odds ratio for individuals experiencing an allergy to a nonantibiotic sulfonamide in those persons with a history of allergy to a sulfonamide antibiotic was 2.8 (95 % CI, 2.1–3.7). Of note, the adjusted odds ratio for the occurrence of a penicillin allergy in a patient with a history of sulfonamide antibiotic allergy was significantly higher at 3.9 (95% CI, 3.5–4.3).

Some limitations of the study included uncertainty of cause and effect of prescribed medications and subsequent reactions, possible inconsistency of physician diagnosis and coding, and lack of precision in the diagnosis of allergic reactions. There is also the possibility of “suspicion bias,” where patients with a history of allergies may be more closely monitored for subsequent reactions than nonallergic patients.

On the other side, small studies reveal little risk of cross-reaction

Researchers involved in a retrospective study of 363 hospital charts examined 34 patients with a self-reported history of sulfa allergy who were subsequently given acetazolamide (a carbonic anhydrase inhibitor), furosemide (a loop diuretic), or both.² The nature of the self-reported sulfa allergic reaction was documented in 79% of the 34 patients. These reported reactions included urticarial rash, nonspecified rash, dyspnea, swelling, nausea or vomiting, throat swelling, red eyes, and bullae. Two patients who were given acetazolamide developed urticaria. No allergic reactions occurred for those patients given furosemide.

The researchers concluded that there was little clinical or pharmacological evidence to suggest that a self-reported sulfa allergy was likely to produce a life-threatening cross-reaction with acetazolamide or furosemide. Small numbers and the lack of a standard definition for an allergic reaction limited the strength of their conclusion.

A small single-blind study of 28 patients with a history of fixed drug eruption to sulfonamide antibiotics examined the usefulness of patch testing as an alternative to controlled oral challenge testing.³ Before patch testing, a sulfonamide antibiotic allergy was confirmed by each patient with an oral challenge of sulfamethoxazole, sulfadiazine, or sulfamethazole. Potential cross-reactivity to several nonantibiotic sulfonamides (including furosemide) was also investigated using controlled oral challenge testing of these agents. Every patient tolerated a subsequent oral challenge with furosemide.

Literature reviews limited by small numbers

Two literature reviews examined the small number of case series, case reports, and “other articles” and concluded little evidence supports the presence of cross-reactivity between sulfonamide antibiotics and non-sulfonamide antibiotics.^3,4 These reviews were limited by their search criteria and lack of explicit critical appraisal.

A literature review of Medline from 1966 to early 2004 revealed 21 case series, case reports, and “other articles” that evaluated the presence of cross-reactivity.³ When the authors of this literature reviewed drilled down to diuretics, they found 5 case reports for cross-reactivity to acetazolamide, 2 case reports for furosemide, 1 case series, and 2 case reports for indapamide (a thiazide diuretic). After reviewing the studies, the authors concluded that little evidence suggested a problem with cross-reactivity either with acetazolamide or furosemide and that there may be an association of cross-reactivity between sulfonamide antibiotics and indapamide. This study was limited by its small numbers and lack of explicit critical appraisal.

In another literature review—in which the main focus was cross-reactivity between sulfonamide antibiotics and celecoxib—the authors concluded that little evidence supported definitive cross-reactivity between sulfonamide antibiotics and diuretics.⁴ The limitations of this study were similar to those of the previous study.

Recommendations from others

The manufacturer insert for furosemide states, under the heading “General Precautions,” that “patients allergic to sulfonamides may also be allergic to furosemide.”⁵ A similar warning occurs for hydrochlorothiazide under the heading “Contraindications.”⁶

Evidence summary

A 2002 Agency for Healthcare Research and Quality systematic review on the diagnosis and treatment of allergic rhinitis found no RCTs comparing antihistamines or nasal corticosteroids with immunotherapy.² Our literature review found 4 studies not included in this report that compared immunotherapy with nasal steroids or oral antihistamines.^3-6 Only 2 of these examined patient-oriented outcomes and both are of poor quality.^3,6 One study reported that inhaled nasal steroid therapy was superior to a nonstandard immunotherapy for ragweed pollen–induced rhinitis.³ The second study allowed patients to choose a treatment arm; it found that immunotherapy was superior to treatment with antihistamines and nasal steroids for patients who chose it.⁶

For patients requiring medication, studies comparing antihistamines with nasal corticosteroids have documented the superiority of intranasal steroids for symptom control of allergic rhinitis.^2,7

The effectiveness of immunotherapy has been documented in more than 40 placebo-controlled trials. However, the patients involved in these trials were often concurrently treated with allergy medications.⁸ In standard practice, immunotherapy is not recommended for most patients with seasonal allergic rhinitis unless avoidance measures and symptomatic therapy are ineffective, have adverse effects, or are not feasible.⁹ Studies indicate that immunotherapy is effective for several years after treatment is discontinued.¹⁰

A review of recent placebo-controlled trials indicates that the risk of developing asthma among patients with allergic rhinoconjunctivitis is significantly reduced when patients receive specific immunotherapy.¹¹ However, allergy immunotherapy presents risk of systemic reactions, with one study reporting a 0.5% risk of systemic reactions per year of therapy.¹²

Recommendations from others

The American College of Allergy, Asthma, and Immunology recommends that effective management of allergic rhinitis may require combinations of medications—antihistamines, decongestants, nasal corticosteroids, and anticholinergic agents as well as aggressive avoidance of rhinitis triggers. Consider allergen immunotherapy in carefully selected patients in consultation with an allergist-immunologist.¹⁰

Evidence summary

A 2002 Agency for Healthcare Research and Quality systematic review on the diagnosis and treatment of allergic rhinitis found no RCTs comparing antihistamines or nasal corticosteroids with immunotherapy.² Our literature review found 4 studies not included in this report that compared immunotherapy with nasal steroids or oral antihistamines.^3-6 Only 2 of these examined patient-oriented outcomes and both are of poor quality.^3,6 One study reported that inhaled nasal steroid therapy was superior to a nonstandard immunotherapy for ragweed pollen–induced rhinitis.³ The second study allowed patients to choose a treatment arm; it found that immunotherapy was superior to treatment with antihistamines and nasal steroids for patients who chose it.⁶

For patients requiring medication, studies comparing antihistamines with nasal corticosteroids have documented the superiority of intranasal steroids for symptom control of allergic rhinitis.^2,7

The effectiveness of immunotherapy has been documented in more than 40 placebo-controlled trials. However, the patients involved in these trials were often concurrently treated with allergy medications.⁸ In standard practice, immunotherapy is not recommended for most patients with seasonal allergic rhinitis unless avoidance measures and symptomatic therapy are ineffective, have adverse effects, or are not feasible.⁹ Studies indicate that immunotherapy is effective for several years after treatment is discontinued.¹⁰

A review of recent placebo-controlled trials indicates that the risk of developing asthma among patients with allergic rhinoconjunctivitis is significantly reduced when patients receive specific immunotherapy.¹¹ However, allergy immunotherapy presents risk of systemic reactions, with one study reporting a 0.5% risk of systemic reactions per year of therapy.¹²

Recommendations from others

The American College of Allergy, Asthma, and Immunology recommends that effective management of allergic rhinitis may require combinations of medications—antihistamines, decongestants, nasal corticosteroids, and anticholinergic agents as well as aggressive avoidance of rhinitis triggers. Consider allergen immunotherapy in carefully selected patients in consultation with an allergist-immunologist.¹⁰

Evidence summary

A 2002 Agency for Healthcare Research and Quality systematic review on the diagnosis and treatment of allergic rhinitis found no RCTs comparing antihistamines or nasal corticosteroids with immunotherapy.² Our literature review found 4 studies not included in this report that compared immunotherapy with nasal steroids or oral antihistamines.^3-6 Only 2 of these examined patient-oriented outcomes and both are of poor quality.^3,6 One study reported that inhaled nasal steroid therapy was superior to a nonstandard immunotherapy for ragweed pollen–induced rhinitis.³ The second study allowed patients to choose a treatment arm; it found that immunotherapy was superior to treatment with antihistamines and nasal steroids for patients who chose it.⁶

For patients requiring medication, studies comparing antihistamines with nasal corticosteroids have documented the superiority of intranasal steroids for symptom control of allergic rhinitis.^2,7

The effectiveness of immunotherapy has been documented in more than 40 placebo-controlled trials. However, the patients involved in these trials were often concurrently treated with allergy medications.⁸ In standard practice, immunotherapy is not recommended for most patients with seasonal allergic rhinitis unless avoidance measures and symptomatic therapy are ineffective, have adverse effects, or are not feasible.⁹ Studies indicate that immunotherapy is effective for several years after treatment is discontinued.¹⁰

A review of recent placebo-controlled trials indicates that the risk of developing asthma among patients with allergic rhinoconjunctivitis is significantly reduced when patients receive specific immunotherapy.¹¹ However, allergy immunotherapy presents risk of systemic reactions, with one study reporting a 0.5% risk of systemic reactions per year of therapy.¹²

Recommendations from others

The American College of Allergy, Asthma, and Immunology recommends that effective management of allergic rhinitis may require combinations of medications—antihistamines, decongestants, nasal corticosteroids, and anticholinergic agents as well as aggressive avoidance of rhinitis triggers. Consider allergen immunotherapy in carefully selected patients in consultation with an allergist-immunologist.¹⁰