Vitamin B12 Deficiency Implicated in Chronic Unexplained Cough

Jacquelyn K. Beals, PhD

December 15, 2009

December 15, 2009 (Buenos Aires, Argentina) — Results of a new study show that sensory neuropathy due to deficiency of vitamin B12 might be a factor in unexplained chronic cough and dysfunction of the pharynx and larynx. Vitamin B12 supplements improved histamine thresholds and significantly raised the cough threshold in patients with vitamin deficiency, but had no effect on control subjects.

The study, presented here at the World Allergy Organization XXI World Allergy Congress by Giuseppe Guida, MD, from Allergy and Clinical Immunology, University of Turin and Mauriziano Hospital in Italy, examined the effect of histamine on the cough threshold and the upper and lower airway responsiveness in patients with unexplained cough.

There are different causes of the chronic cough, said Dr. Guida in his presentation. Among 302 patients with chronic cough seen at their clinic, causes included adverse drug events, cough reflex sensitivity, gastroesophageal reflux disease, and allergic rhinitis; chronic cough of unknown origin comprised about 15% of the patients.

The team of investigators asked whether chronic cough and extrathoracic airway dysfunction might be manifestations of neuropathy. Vitamin B12 deficiency had been previously found to cause peripheral sensory neuropathy in many older patients, said Dr. Guida. Thus, this deficiency was pursued as a possible cause of unexplained chronic cough.

The current study looked at 40 patients with chronic unexplained cough. Of these, 25 were found to have vitamin B12 deficiency (serum levels <300 pg/mL); the control group consisted of 15 chronic-cough patients with no detected nutritional deficiency.

Vitamin B12 deficiency is more common in older individuals, Dr. Guida told Medscape Allergy and Immunology. "Generally, you can find these lower levels of vitamins in older people because they can have some problem with their nutrition."

Vitamin-deficient and control subjects were evaluated with spirometry, and their exhaled nitric oxide was measured. Histamine inhalation was used to assess the bronchial, extrathoracic airway, and cough thresholds. The histamine challenge test can stimulate the airway enough to cause violent coughing. The test causes bronchoconstriction, and patients with hyperresponsive airways react to lower doses of histamine. For this study, hyperresponsiveness was defined as threshold values below 8 mg/mL.

Patients deficient in vitamin B12 were found to have significantly lower threshold values for extrathoracic airway and cough, but bronchial thresholds did not differ from those of control subjects.

B12 deficiency is also known to be accompanied by higher levels of nerve growth factor (NGF), possibly leading to neurogenic inflammation of the airway. Analyses of oropharyngeal biopsies obtained from 6 B12-deficient patients and 3 control subjects revealed significantly higher NGF levels in the epithelial cells of vitamin-deficient patients than in control subjects (P < .02). A graph of the data showed an inverse relation between NGF values and the log of the serum concentration of vitamin B12 (pg/mL).

Vitamin B12 supplementation improved histamine thresholds (reduced hyperresponsiveness) in vitamin-deficient patients without significantly changing them in control subjects. This improvement was found in bronchial (P < .01), extrathoracic airway (P < .001), and cough (P < .01) thresholds.

"Supplementation is certainly very easy to perform . . . by intramuscular injection," Dr. Guida told Medscape Allergy and Immunology. "So, theoretically, there is a good way to treat this disease."

Session comoderator Emilio Pizzichini, MD, PhD, professor of respiratory medicine, director of the Asthma and Airway Inflammation Center, Universidade Federal de Santa Catarina, in Florianópolis, Brazil, seemed skeptical. "That was the first time that I heard anything about vitamin B12 and airway inflammation," he told Medscape Allergy and Immunology. "It's not related as a cause, not that I am aware of. I know about disease of the thyroid and other conditions, but I have never heard about this [effect of] vitamin B12."

"Of course, we need more data to confirm the fact that there is a strong association between these 2 cofactors [chronic cough and the B12 deficiency]," acknowledged Dr. Guida. However, "if this is the case, [this] could be a very easy way to help these people," he said, "especially because they are older and it's a very easy medication to [administer]."

Dr. Guida and Dr. Pizzichini have disclosed no relevant financial relationships.

World Allergy Organization XXI World Allergy Congress (WAC): Abstract 290. Presented December 8, 2009.

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