Antihistamines may offer hope for long COVID patients

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the ongoing pandemic of coronavirus disease 2019 (COVID-19), led to an enormous disruption of the global economy. Over 413 million cases of COVID-19 have been reported as of February 15, 2022, with 5.8 million deaths.

Even among those who have recovered from COVID-19, many experience post-acute sequelae of COVID-19 (PASC), which has no accepted definition or treatment. Healthcare providers, already struggling with the demands of handling the pandemic while simultaneously carrying out other urgent medical work, have little time to investigate the vague and protean manifestations of PASC, and even less to look into possible treatment avenues.

In a recent The Journal for Nurse Practitioners paper, researchers offer hope that an inexpensive over-the-counter (OTC) medication could improve PASC symptoms for a large proportion of these patients.

Study: Antihistamines for Postacute Sequelae of SARS-CoV-2 Infection. Image Credit: megaflopp /

Study: Antihistamines for Postacute Sequelae of SARS-CoV-2 Infection. Image Credit: megaflopp /


PASC may precipitate a global health crisis as a result of the chronic pain, weakness, and loss of function associated with this condition. In the United States, about two in three hospitalized COVID-19 patients develop PASC within six months. Comparatively, among non-hospitalized patients, over 10% have chronic symptoms that remain after six months.

It is estimated that worldwide there are 54 million people with PASC. In the absence of any treatment guidelines, the current paper reports two women with PASC who responded to antihistamines.

Study findings

The first patient, a White healthcare worker in her forties, had multiple health conditions, including idiopathic Raynaud phenomenon, polycystic ovarian syndrome, and dairy allergy.

She typically exercised hard on four to five days every week. After exposure to SARS-CoV-2 in January 2020, the patient developed flu-like symptoms within 72 hours. Within the next ten days, she reported developing a rash, chest pain, ulcerations in the mouth, dry cough, and night sweats, along with loss of taste.

While the acute illness subsided partially within 24 days, other symptoms persisted sporadically, along with bruising and oral ulcers. These symptoms occurred in clusters, though not always at the same time.

In March 2020, the patient developed brain fog, again with a waxing and waning pattern. Antibody testing in June 2020 was negative. The patient was then evaluated by several different specialists without any remarkable findings to explain her symptoms, including electrocardiogram, blood tests, and imaging tests.

One year later, the patient was re-evaluated for her skin rash and oral ulceration, showing lymphocytic and neutrophilic infiltration at both biopsy sites.

She first took diphenhydramine for allergic symptoms following cheese consumption in June 2020 and found a major reduction in tiredness and brain fog the next morning. After 72 hours, during which she did not take the medicine again, and again felt tired and fogged, she repeated the dose and again observed improvement.

The patient then continued the same drug for six months and was then put on another drug, hydroxyzine. At the lowest dose of hydroxyzine, she had significant improvement in rashes, tiredness, and cognitive function. After doubling the dose, which was still only a third of the maximum permitted dose, she achieved almost complete symptomatic relief.

At the time of the study, the patient had taken hydroxyzine for nine months with a significant long-term return to pre-PASC exercise and cognitive function, while other symptoms were mostly relieved. She rates her functioning as 90% of the level before PASC/

The second patient, a White teacher, was a healthy and active middle-aged woman with asthma and seasonal allergies, for which she took fexofenadine. After 48 hours of developing COVID-19-like respiratory symptoms, this patient reported body pain, a dry cough, and fever, though a polymerase chain reaction (PCR) for SARS-CoV-2 was negative.

Additional symptoms developed, including chest pain and breathlessness, leading to a clinical diagnosis of COVID-19. She then developed fever and joint pain with breathlessness over the next few weeks that lasted for about three months. At this point, the antibody test was negative.

A month later, this second patient had tachycardia, toe symptoms, tiredness, joint pain, bouts of taste and smell alterations, and brain fog, all of which remained for nine months. She also developed abdominal pain and bloating, as well as acrocyanosis of both hands. Recognizing the potential for a microvascular thrombotic origin, the patient started to take five tablets of 81 mg of aspirin each day, which allowed the acrocyanosis to be relieved in two days.

The second patient continued with a single dose of 81 mg aspirin per day, along with probiotics and vitamins. At 13 months, a shift to diphenhydramine because of the non-availability of fexofenadine led to a marked resolution of her brain fog and tiredness. She kept taking this medicine and found that her symptoms improved markedly after two doses, thereby allowing her to resume her pre-PASC exercise regimen.


The case studies demonstrate how PASC presents experience debilitating and life-altering symptoms, often waxing and waning, that lasted for over a year in both cases. However, treatment with an easily available OTC antihistamine normalized life in both cases.

Antihistamines have proven to arrest symptom progression and boost survival in patients with critical COVID-19. In fact, famotidine was linked to lower levels of immunologic activation, which may indicate that histamine antagonists reduce the chances of a cytokine storm.

Significantly more research is needed to determine how and which drugs to use and whether first- or second generations should be used singly or together. However, the widespread distribution of receptors for SARS-CoV-2 in the body makes it possible for any organ system to be affected by the inflammation and endothelial activation caused by the infection. This fits the observed wide spectrum of PASC symptoms.

Patients are desperately searching for something to help them get back on their feet. Currently, there is no cure for PASC, only symptom management. The possibility that an easy-to-access, over-the-counter medication could ease some of the PASC symptoms should offer hope to the estimated 54 million people worldwide who have been in distress for months or even years.”

Journal reference:
  • Pinto, M. D., Lambert, N., Downs, C. A., et al. (2022). Antihistamines for Postacute Sequelae of SARS-CoV-2 Infection. The Journal for Nurse Practitioners. doi:10.1016/j.nurpra.2021.12.016.
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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