Hair Loss After Routine Immunizations

JAMA, October 8, 1997–Vol 278, No. 14
Robert P. Wise, MD, MPH; Kitonga P. Kiminyo, MD; Marcel E. Salive, MD, MPH

Context.–Alopecia is a recognized adverse effect of numerous medications, but vaccines are not normally considered a cause for unexpected loss of hair.
Objective.–To describe case reports of hair loss after routine vaccines and to assess the hypothesis that vaccinations might induce hair loss.
Design.–Case series with telephone follow-up.
Methods.–Review of spontaneous reports to the Food and Drug Administration, the Centers for Disease Control and Prevention, and the Vaccine Adverse Event Reporting System.
Main Outcome Measure.–Loss of hair following immunization.
Results.–A total of 60 evaluable reports submitted since 1984 and coded for "alopecia" after immunizations included 16 with positive rechallenge (hair loss after vaccination on more than 1 occasion), 4 of which were definite and 12 possible or probable. Of the 60 cases, 46 had received hepatitis B vaccines. Both of the currently available recombinant products, as well as the former plasma-derived product, were represented. Females predominated in all age groups. The majority of patients recovered, but clinical features, such as intervals from vaccination until onset and the extent and reversibility of hair loss, varied widely. Nine patients reported previous medication allergy.
Conclusion.–There may be an association, probably very rare, between vaccinations and hair loss. More than 1 pathophysiologic mechanism may be responsible. Since apparently nonrandom distributions by vaccine, age, and sex could reflect biased case ascertainment, further research will be needed in defined populations with consistent case detection.

JAMA. 1997;278:1176-1178
Vaccine coverage depends on public confidence in the safety of routine immunizations. Manufacturers and regulatory agencies attempt to identify risks of new pharmaceutical products before they are licensed, but constraints, such as the relatively small number of subjects in clinical trials, limit discovery of adverse effects.1,2 Therefore, postlicensure safety surveillance is essential.

In early 1994, a concerned mother telephoned the Food and Drug Administration (FDA), describing her young daughter’s experience of nearly total loss of scalp hair after her second and third doses of hepatitis B vaccine (HBV). Following this index report of recurrent hair loss after routine childhood vaccinations (patient 1, below), we reviewed national vaccine safety surveillance systems for additional cases.

Methods
We found cases of hair loss after vaccinations dating back to 1969 in national surveillance systems for vaccine adverse events: the current Vaccine Adverse Event Reporting System (VAERS)3 and prior data from the FDA, the Centers for Disease Control and Prevention (CDC), and product manufacturers. Five excluded reports lacked sufficient detail. In 60% of cases, we interviewed the patient, a parent, or a physician, usually by telephone, for further details.

Results
The investigation yielded 60 reports with varying degrees of hair loss. The index patient and 3 others described clear positive rechallenge for hair loss (recurrence following readministration: of a suspect product):
Patient 1.–A 12-month-old white female infant in California began to lose scalp hair 10 days after her second immunization with HBV. During the next 3 months, she progressed to complete baldness, but regrowth was complete by the age of 18 months. Approximately 1 week after her third dose of HBV, given with oral polio vaccine (OPV) a the age of 18 months, her parents noticed recurrent hair loss, which again progressed to near total loss of hair and which regrew beginning at the age of 2 years. Extensive medical evaluation failed to identify a cause. Her physicians considered, but discounted, the possibility that recent vaccination might have contributed, since she had experienced no adverse event after her first dose of HBV at the age of 10 months, and there was no suggestion in the medical literature or product package labeling that hair loss might follow vaccination.

Patient 2.–A 17-day-old white female neonate received her first dose of HBV. Slight hair loss was observed 36 days later. She received first doses of diphtheria-tetanus-pertussis (DTP) vaccine, Haemophilus influenzae type B conjugate vaccine (HIBV), and OPV at the age of 2 months without apparent incident. Her second doses of DTP, HBV, HIBV, and OPV at the age of 4 months were followed after 1 to 2 weeks by development of complete alopecia. Third doses of DTP and HIBV were given at 6 months of age with complete regrowth of hair by the age of 9 months, when her third dose of HBV, given alone, was followed by recurrence of complete alopecia within 1 week, as well as a dry, red, scaly, eczema-like rash on her left arm. She lost eyebrows and lashes at the age of 13 months, 5 weeks after her first tuberculosis tine test. Partial sparse hair regrowth was noted (but not eyebrows or lashes) at 16 months of age, but this hair was also shed 2 months later when she received DTP, HIBV, and OPV. Her eyebrows later grew back, but not most of her lashes.

Patient 3.–Within 1 day after her first dose of HBV, a 30-year-old female nurse developed mild hair loss, arthralgias, fatigue, and weakness, which lasted 1 week. One month later, her second dose was followed 1 day later by recurrent onset of hair loss and, about 2 weeks later, by recurrent arthralgias, fatigue, and weakness. Alopecia progressed for a few months until she estimated that half of her hair remained in a diffuse distribution with a thinned appearance. Her hair later regrew without treatment or workup.

Patient 4.–A 56-year-old white women using bronchodilators and taking thyroxine received influenza virus vaccine. Ten weeks later she developed hair loss affecting her scalp and axillae. The results of a scalp biopsy were reportedly negative. Topical minoxidil had little effect. She recalled severe hair loss 1 year earlier when she received influenza virus vaccine. She also had a history of hair loss 6 years earlier associated with stressful employment and recovery after 6 months of topical minoxidil therapy.

Another 12 patients had possible or probable positive rechallenges. Exposure to chemical and mechanical hair treatments confounded 1 patient’s hair loss. Documentation for the other 11 did not clarify whether initial postvaccinal hair loss had resolved before the second vaccination. Three of the 4 clear positive rechallenge cases and all 12 of the possible positive rechallenges followed vaccinations against HBV (Table). Hair loss worsened in 6 of the 12 after a second vaccination.

An increase since 1991 in hair loss onset dates among all 60 cases (Figure) probably reflects effects of educational publicity about the VAERS start-up in 1990 and universal vaccination against hepatitis B virus in 1991.4
Patient ages varied from 2 months to 67 years, with females accounting for 49 of 59 patients of known sex. Fewer than a third of reports described patients younger than 18 years. Eleven of 16 children whose reports specified their sex were girls.

Fifty-six US reports were from 20 states. California, with 10 patients, is the most populous state and was the site of local publicity about the index case.5 (Five reports from areas within commuting distance of San Francisco were reported within 3 months after this article appeared.) Eight of 9 cases from Illinois were black female health care workers (7 nurses and a pharmacist) reported together from 1 hospital. A consulting dermatologist attributed the hair loss in all 8 cases to cosmetic hair chemicals and traction.

Intervals from vaccination to onset of hair loss were provided in 50 reports, with 84% within approximately 1 month. (Hair loss reportedly began within 1 day after immunization in 5 cases.)

The extent and duration of hair loss varied widely among 37 reports with sufficient data to classify. Sixteen patients reported severe alopecia (extensive hair loss over more than half of the head or body); 8 recovered most or all of their hair; and 4 had persistent baldness. Recovery status remains unknown in 4 cases. Eighteen patients reported mild to moderate hair loss (most hair still intact). Nine had full resolution, 1 did not, and 8 were unknown. Two of 3 ambiguous histories of hair loss included full recovery.

Three patients had histories of past hair loss without linkage to immunizations. Nine reported allergy to medications.

Hepatitis B vaccine, identified in 46 cases, was the most frequently cited vaccine exposure (Table). It was given alone in 40 cases. Both recombinant products and the earlier plasma-derived vaccine were represented.

Comment
This case series, particularly the 4 cases of hair loss with clear positive rechallenge, provides evidence consistent with a causal relationship to vaccinations.6-12 Hair loss was the central feature in 45 cases, including all 4 of the clear positive rechallenges.

The heterogeneous vaccine exposures and subsequent clinical manifestations suggest that more than 1 vaccine and pathophysiologic mechanism could trigger or contribute to hair loss following vaccination. Hepatitis B vaccine alone preceded hair loss in 40 patients, but 14 reported no HBV exposure, including 1 with positive rechallenge after influenza virus vaccine. Cases varied markedly in hair loss severity, intervals to onset, and recovery. Several reported additional symptoms, notably arthralgia or arthritis in 9 patients.

Vaccines are not usually identified among antecedents to hair loss,13 although Petkov et al14 described a 32-year-old man with a history of neurodermatitis with initial onset of fever, lymphadenopathy, and alopecia areata 5 days after smallpox vaccination. We hypothesize that vaccine antigens may be capable of triggering hair loss, either via telogen effluvium or through a novel autoimmune-mediated mechanism.

Recent reviews^1,15,16 of drug-induced hair loss implicate numerous other pharmaceutical agents via either of 2 pathophysiologic mechanisms. Anagen effluvium refers to a direct cytotoxic effect on the rapidly dividing hair follicle cells, common with chemotherapeutic agents for malignancies (which did not confound our cases). Onset of hair loss follows the drug insult after a short lag of days to weeks.

Telogen effluvium, a usually reversible response to pharmacologic or physiologic stress, could account for some of our cases. Large fractions of follicles cells enter the resting phase (telogen), followed some 1 to 3 months later by widespread shedding when they reenter the active hair synthesis phase (anagen) together. Recognized triggers include several medications, high fevers, hormonal changes, hemorrhage, and others. Although many of our cases had much shorter intervals from vaccination to onset of hair loss than the weeks to months typical in telogen effluvium, most of our intervals were approximate. Further, intervals were likely to be reported with reference to the most recent vaccination. But telogen effluvium might have been triggered by a prior immunization. In patient 2, for example, the first episode of total hair loss began less than 2 weeks after second doses of 4 vaccine products, but this onset date also corresponds to a 4-month interval since the first doses of 3 vaccines. Similarly, the second episode followed HBV by less than a week, corresponding as well to a 3-month lag after third doses of DTP and HIBV. Thus, both episodes could be consistent with telogen effluvium rather than relatively acute responses to the more proximate doses of HBV.

In addition to the possible role of telogen effluvium, we propose that immunologic mechanisms should also be considered. Although other immunologic drug reactions are well known,13,17,18 and autoimmunity is hypothesized as the underlying cause of alopecia areata,19-21 immunologic mechanisms have not been implicated in hair loss as an adverse effect of medications.1,15-17 We speculate, however, that cell growth cycles might be pathologically modulated by vaccine-induced antibodies. This scenario suggests antigenic similarities between vaccines and hair follicles, at least in susceptible patients, that should be investigated.

Unexpected hair loss could occasionally follow vaccine exposures by chance alone, since vaccine exposures are extremely common, and unexplained hair loss (alopecia areata or other syndromes) is not rare. The reported rate of 20.2 cases of alopecia areata per 100,000 in Olmsted County, Minnesota,19 would translate to 50,000 US cases per year. However, the positive rechallenges and distinctive distributions by age, sex, and vaccines in our case series appear unlikely to have arisen by chance alone. Olmsted County age-adjusted rates did not differ by sex (20.3 for females and 19.9 for males), and most rates in 10-year age groups were between about 19 and 29 per 100,000 person-years. In contrast, the majority of our cases (34 of 39 adults) were women whose hair loss followed immunizations with only one of several common vaccine types.

Hair loss is reported very rarely following immunizations. Although under-reporting commonly characterizes passive surveillance, the FDA has learned of fewer than 5 cases per year during a decade in which Americans received roughly 1 billion vaccine doses. Even when hair loss occurs after vaccination, it is often mild or moderate and self-limited. Apart from cosmetic implications, the worst consequences may be anxiety and costs for medical evaluation, secondary effects that may be reduced through dissemination of this information.

We cannot dismiss possible biases in case ascertainment. Health care workers are a primary target group for HBV. Among 39 adult cases, half (19) were nurses, physicians, or other medical personnel; women accounted for 17 of the 19. Employees in this field may be more likely to suspect recent immunization when they develop hair loss, and they are familiar with the importance of reporting adverse events. Sex-specific bias might also have affected reporting. Men noticing hair loss might more often attribute it to male pattern baldness.

A patient with hair loss possibly linked to antecedent immunization must decide, with physician and family, whether to receive remaining routine vaccinations. At present, we believe that the risk of additional vaccinations for patients who have lost hair once after immunization should be judged individually, weighing an uncertain risk that hair loss could recur against clear benefits of protection from target diseases.

After reviewing 60 case reports, we believe that immunizations warrant consideration among potential causes of hair loss. Further investigation of possible associations between vaccines and loss of hair has begun in the Vaccine Safety Datalink,22 where several health maintenance organizations facilitate investigations of immunization safety by pooling vaccination, hospital discharge, and other health service data.