Recognition & management of varicella infections and accuracy of antimicrobial recommendations: Case vignettes study in the US.

BACKGROUND: In 1995, the CDC recommended one-dose routine varicella immunization for children <12 years of age, expanding its recommendation to two doses in 2006. Today, with widespread varicella vaccination coverage, an estimated 3.5 million cases of varicella, 9,000 hospitalizations, and 100 deaths are prevented annually in the United States. Since varicella infections are now uncommon, health care providers (HCPs) may not recognize varicella infections and may prescribe inappropriate treatment.
METHODS: An online survey of HCPs was conducted to assess recognition and management of varicella infections. Responses to eight varicella vignettes describing patients with varying varicella symptoms were analyzed and descriptive analyses performed. Stratified analysis comparing responses of those licensed before and in/after 1996 was also performed.
RESULTS: 153 HCPs (50 nurse practitioners, 103 doctors) completed the survey. Mean age of respondents was 44 years. 62% were female, and 82% were licensed before 1996. Varicella infection was correctly diagnosed 79% of the time. HCPs correctly recognized uncomplicated varicella vignettes 85% of the time versus 61% of the time for complicated varicella vignettes. Antibiotics were recommended 17% of the time and antivirals 18% of the time, of which 25% and 69% (respectively) were not appropriate per guidelines. HCPs licensed before 1996 were better able to recognize varicella compared to those licensed later, but prescribed more antimicrobials medications to treat varicella.
CONCLUSIONS: Although most HCPs recognized varicella infection, a sizable proportion could not recognize cases with complications, and some of the varicella cases were inappropriately treated with antibiotics and/or antivirals. Additional HCP training and high vaccination coverage are important strategies to avoid inaccurate diagnoses and minimize unnecessary exposure to antimicrobial/antiviral therapies.

Introduction

Varicella infection was common in the United States (US) in the pre-vaccination era, with 4 million varicella cases, 10,000 hospitalizations, and 100 deaths related to varicella occurring annually in US children [1]. Introduction of the varicella vaccination program in 1995 was a major milestone in the fight against this disease, with the Advisory Committee on Immunization Practices (ACIP) recommending 1 dose for routine childhood varicella vaccination and catch-up for children up to 12 years, and 2 vaccine doses for older susceptible persons at greater risk (≥ 13 years of age) [2]. In 2006, ACIP expanded the recommendation to two doses for all children, and adolescents/adults without evidence of immunity [2]. Fifteen years of vaccination (1996 to 2010) allowed the US to demonstrate a dramatic decrease in the annual burden of disease with 20 varicella related deaths (90% decrease compared to pre-vaccine era), 1,700 hospitalizations (84% decrease) and 350,000 varicella cases (92% decrease) in 2010 [1]. It is estimated that the varicella vaccination program saves $373 million in direct cost and $1.598 billion in societal costs, annually in the US [3].

Varicella is highly transmissible with 90% of susceptible household contacts developing varicella after exposure [4]. Most varicella cases resolve without complications, especially among the immunocompetent. However, moderate and serious complications can occur, including pneumonia, bacterial superinfections involving skin and soft tissues, cerebella ataxia, encephalitis and in rare cases, may lead to death [5,6]. Though varicella can also occur among the vaccinated (called breakthrough varicella), such infection is milder, of shorter duration, and more likely to be maculopapular (versus typical vesicular) when compared to the unvaccinated, especially after two- dose vaccination [4]. Most cases of varicella infections can be managed with only supportive care [7]. Cases with complications may require more aggressive management, including use of prescription antivirals and/or antibiotics, and occasionally hospitalization [8]. The American Academy of Pediatrics (AAP) notes that antivirals are primarily recommended for use with populations at increased risk for complications, including immunocompromised individuals [9].

Despite the high rate of vaccination and resulting steep decline in varicella cases over the past several decades, growing hesitancy to childhood vaccinations [10] and delays in vaccinations due to the current COVID-19 pandemic, raise concerns about a potential increase in vaccine preventable diseases, including varicella, in the coming years [4,10,11]. Yet, because of its rarity today, many health care providers (HCPs) who began working after the advent of widespread vaccination may neither recognize varicella infection nor readily implement appropriate treatment. Given the current dynamics, we undertook a study to evaluate the extent to which today’s HCPs recognize and manage varicella infections among children in the US.

Methods

An online survey of HCPs using a clinical case vignette strategy was conducted. Ten case vignettes were drawn from existing literature [12-14] and developed in consultation with infectious disease experts. The vignettes included brief case descriptions and had accompanying medical case images. Nine of the 10 vignettes were true varicella infections, while one represented separate skin infection to ensure clinicians were able to accurately diagnosis varicella versus other similar infectious diseases. The vignettes varied in the age (1–15 years), health profiles, clinical presentations, childhood vaccination status, and presence of complications. Correct diagnosis (varicella with or without complications) and appropriate disease management was defined for each vignette using the American Academy of Pediatrics (AAP) Red Book, clinical infectious disease expert input, and literature [14].

HCPs were recruited by a survey vendor specializing in health care provider research with physicians and nurses from their existing panel of healthcare professionals (HCPs) across the United States. Respondents were invited via email to take part in the survey. Inclusion criteria included: either a board-certified physician in Pediatrics/ Family medicine/ Internal Medicine specialties, treating at least 100 pediatric patients per month or a licensed nurse practitioner; currently practicing in the United States with ≥ 50% time spent in a clinical setting; English proficiency; and consent to participate. The survey was administered through an on-line portal. All participants received a modest incentive for their participation and were blinded to the study sponsors. Anonymized respondent data was delivered for analysis to prevent responses being linked directly to individual providers. This study was determined to be exempt from Institutional Review Board (IRB) oversight by Advarra IRB; all respondents reviewed and approved an informed consent document on-line prior to completing the survey.

None of the respondents were told that the study was about varicella vaccination, but rather that the survey was about treatment patterns of pediatric patients with various viral and bacterial infections, to avoid respondent bias. Respondents were presented with each case vignette, including a brief description of the case, the age of the child, childhood vaccination status, and an image of the skin lesions and asked to select a diagnosis from a pre-populated list of potential skin infections including many with similar clinical presentations (Table 1a). If a respondent selected varicella, they were then asked to indicate if they believed the case was accompanied by any complication. Following diagnosis, respondents were presented with a list of potential disease management strategies ranging from supportive care to inpatient hospitalization, though only antiviral and antibiotic treatment is in scope for this manuscript. Respondents were permitted to select more than one management or treatment approach (Table 1b). Additionally, information on the respondents’ training, working environment, age, gender, and other demographics were collected. Both physicians and nurse practitioners responded to the same survey. Respondent data were analyzed descriptively overall and stratified by whether the HCPs were licensed prior to or after the introduction of the varicella vaccine in 1995.

Table 1

a. List of Potential Diagnoses Options. b. List of Potential Management Strategies *.

Based on the case description above, what do you feel is the most likely primary diagnosis? [Select one]

Varicella [SHOW sub-options if Varicella is selected]

▪ Varicella without complication

▪ Varicella with complications

• Varicella meningitis

• Varicella encephalitis and encephalomyelitis

• Varicella myelitis

• Varicella pneumonia

• Varicella keratitis

• Other varicella complications

Hand foot and mouth disease

Bacterial infection NOS

Pruritus, unspecified

Impetigo

Scabies

Poison oak/ivy

Molluscum contagiosum

Folliculitis

Conjunctivitis

Cellulitis

Other

Based on the case description above, what treatment strategy would you recommend and/or prescribe? [Select all that apply] **

Supportive care

Administer varicella vaccine

Administer pneumococcal vaccine

Administer varicella immunoglobulin

Other catch-up vaccines

Treatment with antivirals

Treatment with antibiotics

Hospitalization

▪ Manage as outpatient

▪ Admit for inpatient treatment

Laboratory tests

Imaging

Other

*Note: Only the antibiotic and antiviral usage was in scope for this manuscript;

** Please see the supplement for a copy of the survey.

*** Supportive care (select all that apply): Acetaminophen, Ibuprofen, Calamine lotion, Colloidal oatmeal bath, Zinc oxide, Topical antihistamines, Topical corticosteroids, Topical antifungal, Antiseptic cleansers (hydrogen peroxide, chlorhexidine etc.), Topical antibiotics, Warm compresses to relieve itching and pain, Other supportive care.

The final eight vignettes are shown in Table 2 and the survey provided in the supplement. Two of the 10 vignettes were excluded from the final analysis (and from Table 2; details are provided in the supplement) after consultation with two clinicians/ experts. Of the eight varicella cases for which respondent data was evaluated, two of which were defined as having complications. Among the cases, supportive care alone was appropriate for four vignettes. Antibiotics in addition to supportive care were appropriate for two vignettes, and antivirals for another two vignettes (Table 2).

Table 2

Summary of case vignettes*.

Vignette	Age and health status	Varicella vaccination status	Diagnosis	Primary Treatment Recommendation ***
1	Healthy 3.5-year-old	Unvaccinated, no known exposure to varicella	Varicella with no complications	Supportive care
2	Healthy 5-year-old	1-dose vaccination, exposed 14 days prior	Varicella with no complications	Supportive care
3	Healthy 7-year-old	Unvaccinated, not exposed to varicella	Varicella with Complication (S. aureus infection of lesions)	Antibiotics+/- Supportive care
4	3-year-old with history of asthma and on prednisone	Unvaccinated, exposed to shingles 7 days prior	Varicella with no complications	Antivirals+/- Supportive care
5	Healthy 10-month-old	Unvaccinated, exposure to varicella 12 days prior	Varicella with no complications	Supportive care
6	Healthy 15-year-old	Unvaccinated (personal belief exemption), exposure to varicella 10 days prior	Varicella with no complications	Antivirals+/- Supportive care
7	Healthy 6-year-old, respiratory sign/symptoms.	1-dose vaccination, no known exposure to varicella	Varicella withComplication (pneumonia)	Antibiotics+Hospitalization+/- Supportive care
8	Healthy 14-year-old	Unvaccinated (religious belief exemption), no known exposure to varicella.	Varicella with no complications	Supportive care

*Copy of the survey provided in the supplement

** 2 vignettes were removed from the analysis after consultation with the clinical consultants due to concerns about unclear treatment option based on vignettes to avoid potential confusion.

*** The scope of the manuscript was restricted to correct antibiotic and antiviral usage regarding the treatment option.

Results

Study sample

The study population consisted of 103 physicians, and 50 nurse practitioners, totaling 153 respondents. Mean age of respondents was 43.9 years with the majority being female (62.1%), White (73.9%) and licensed in the post-vaccination era of 1996 or later (81.7%) (Table 3).

Table 3

Respondent descriptions.

	Licensed prior to 1996	Licensed in 1996 or later	Total (N = 153)
Provider type
Physician	22 (21.4%)	81 (78.6%)	103 (67.3%)
Nurse Practitioner	6 (12.0%)	44 (88.0%)	50 (32.7%)
Age, mean (SD)	59.8 (6.8)	40.4 (7.9)	43.9 (10.9)
N missing	3	13	16
Gender
Female	13 (46.4%)	82 (65.6%	95 (62.1%)
Male	15 (53.6%)	41 (32.8%)	56 (36.6%)
I prefer not to answer	0 (0.0%)	2 (1.6%)	2 (1.3%)
Race
Asian	2 (7.1%)	15 (12.0%)	17 (11.1%)
Black/African American	0 (0.0%)	6 (4.8%)	6 (3.9%)
White	25 (89.3%)	88 (70.4%)	113 (73.9%)
2+ races	0 (0.0%)	2 (1.6%)	2 (1.3%)
Don’t know/Not sure	0 (0.0%)	1 (0.8%)	1 (0.7%)
Prefer not to answer	1 (3.6%)	13 (10.4%)	14 (9.2%)

Recognition of varicella

When presented with the eight vignettes, 79.2% of respondents accurately recognized varicella infection. (Table 4) Those licensed in the pre-vaccination era were more likely to recognize varicella infection (88.8%) compared to those licensed in the post-vaccination era (77.1%). Among respondents who accurately recognized varicella infection, the majority (86.7%) accurately categorized the infection as uncomplicated or complicated. Respondents licensed in the pre-vaccination era correctly recognized complication status 87.4% of the time, similar to those licensed in the post-vaccination era (86.5%). Among the 254 responses where varicella infection was not correctly identified, bacterial infection, not otherwise specified (24.8%), “other” (20.1%), impetigo (19.3%), and hand, foot & mouth disease (12.2%) were the most common diagnoses selected.

Table 4

Varicella diagnosis and categorization.

	COLUMN A: Vignettes where Varicella was correctly diagnosed*			COLUMN B: Vignettes where presence or absence of complications was correctly identified**
	All Responses#	Licensed <1996	Licensed 1996-present	All Responses	Licensed <1996	Licensed 1996-present
	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
All Responses (8 vignettes)	970 (79.2%)	199 (88.8%)	771 (77.1%)	841 (86.7%)	174 (87.4%)	667 (86.5%)
Varicella vignettes with no complications (6 vignettes)	784 (85.4%)	159 (94.6%)	625 (83.3%)	167 (89.8%)	136 (85.5%)	538 (86.1%)
Varicella vignettes with complications (2 vignettes)	186 (60.8%)	40 (71.4%)	146 (58.4%)	674 (86.0%)	38 (95.0%)	129 (88.4%)
Vignette 1—Varicella with no complications	125 (81.7%)	26 (92.9%)	99 (79.2%)	112 (89.6%)	25 (96.2%)	87 (87.9%)
Vignette 2—Varicella with no complications	128 (83.7%)	25 (89.3%)	103 (82.4%)	120 (93.8%)	23 (92.0%)	97 (94.2%)
Vignette 3—Varicella with complication (Staphylococcus aureus infection complication of lesion)	64 (41.8%)	15 (53.6%)	49 (39.2%)	45 (70.3%)	13 (86.7%)	32 (65.3%)
Vignette 4—Varicella with no complications	123 (80.4%)	27 (96.4%)	96 (76.8%)	65 (52.8%)	11 (40.7%)	54 (56.3%)
Vignette 5—Varicella with no complications	133 (86.9%)	27 (96.4%)	106 (84.8%)	130 (97.7%)	25 (92.6%)	105 (99.1%)
Vignette 6—Varicella with no complications	144 (94.1%)	28 (100%)	116 (92.8%)	134 (93.1%)	28 (100%)	106 (91.4%)
Vignette 7—Varicella with complication (pneumonia)	122 (79.7%)	25 (89.3%)	97 (77.6%)	122 (100%)	25 (100%)	97 (100%)
Vignette 8—Varicella with no complications	131 (85.6%)	26 (92.9%)	105 (84.0%)	113 (86.3%)	24 (92.3%)	89 (84.8%)

* N refers to total number of vignettes and not the number respondents. Thus, the total number of vignettes in the survey is 153 respondents * 8 vignettes each = 1224 vignettes. Of these, only the ones correctly diagnosed are reported here. There was no missing vignette for any respondent.

** Percentage out of those who correctly diagnosed varicella in Column A.

For varicella vignettes with no complications, correct recognition of varicella infection ranged from 80.4% to 94.1%. Once identified as varicella, most respondents were able to categorize the cases as lacking complications (89.6% to 97.7%), except for vignette #4, where nearly half incorrectly believed the case had complications (47.2%). Varicella cases with complications were more difficult to identify as varicella infection. For vignette #3, a varicella with complication (Staphylococcus aureus infection), only 41.8% of respondents recognized varicella infection accurately; among those accurately diagnosing varicella, 70.3% identified the vignette as having a varicella related complication. For vignette #7, a varicella with complication (pneumonia), 79.7% of respondents recognized varicella infection accurately; 100% of all respondents who recognized varicella infection accurately identified the case as having complications.

Treatment patterns: Use of antivirals and antibiotics

The treatment patterns regarding the use of antivirals and antibiotics for the varicella vignettes with and without complications are shown in Table 5.

Table 5

Use of antivirals and antibiotics for vignettes with and without complications.

Antiviral and antibiotic Treatment patterns	Varicella without complications*		Varicella with complications**
	Actual survey response	Expected use per guidelines	Actual survey response	Expected use per guidelines
Proportion prescribed antivirals	15.9%	50.0% $	14.1%	0.0%
Proportion prescribed antibiotics	5.0%	0.0%	41.5%	50.0% $$
Proportion prescribed both antibiotics and antiviral	0.4%	0.0%	8.5%	0.0%
Proportion prescribed neither antibiotics and antiviral	78.6%	50.0%	35.9%	50.0%

*Varicella without complications (From vignettes # 1,2,4,5,6,8);

** Varicella with complications (From Vignettes# 3 and 7).

$ Vignettes 4 and 6 needed antivirals;

$$ Vignettes 3 and 7 needed antibiotics.

Appropriate antiviral and antibiotic use

While 75.4% of antibiotic recommendations were correctly made for two vignettes with complications of varicella, 24.6% of antibiotic recommendations were incorrectly assigned to cases where either supportive care or antiviral therapy were appropriate. Of all antiviral recommendations, only 30.6% were appropriate to the case described (Fig 1).

Fig 1

Percent of correct vs. incorrect treatment recommendations by type of intervention.

HCPs licensed in the pre-vaccination era recommended antibiotics and antivirals more often as compared to those licensed in later years (22.8% and 32.1% versus 12.4% and 12.0%). Antibiotics were incorrectly recommended 31.4% of the time by those licensed in the pre-vaccination era compared to 22.4% of the time among those licensed in the post-vaccination era (Fig 2). Conversely, antivirals were incorrectly recommended less often by HCPs licensed earlier (63.9%) compared to those licensed later (72.1%).

Fig 2

Percent of incorrect treatment recommendations by type of intervention by year of licensure.

Discussion

This study examined diagnostic and antiviral/antibiotic prescription practices for varicella infection in the age of widespread vaccination in the US. Many HCPs today have little experience with varicella infection due to rarity of the disease given widespread use of vaccines. However, vaccine hesitancy [15] and delays in routine pediatric vaccination due to COVID-19 [11] has impacted the vaccination patterns and coverage rates. It is important to accurately diagnose and manage pediatric infectious diseases such as varicella. This study demonstrated that while most varicella cases without complications are correctly identified by HCPs, significantly fewer HCPs were able to correctly recognize varicella when presented with complications.

Our study also showed that some varicella cases may be inappropriately treated with antibiotics and antivirals. The CDC estimates that one in three antibiotic prescriptions in the United States is unnecessary [16] Other countries also show high use of antibiotic use in varicella [8]. While our research does not try to evaluate antibiotic resistance directly, inappropriate use of antibiotics for management of varicella may further contribute to antimicrobial resistance, which is an on-going public health challenge [17,18]. It must be noted that in large part, HCPs accurately assigned management approaches for most vignettes. Supportive care was appropriately recommended as the primary approach for most cases.

Of particular interest is the finding that HCPs trained prior to widespread vaccination were better able to recognize varicella infection in patients and correctly determine presence of complications, but prescribed antibiotics and antivirals more often than recommended. This finding is consistent with previous studies investigating antibiotic prescribing patterns which have demonstrated that older HCPs prescribed a higher volume of antibiotics [19,20].

While this study points to important diagnostic and antimicrobial treatment patterns for varicella infection in an era of widespread vaccination, the study does face certain methodological limitations. Due to limited number of varicella infections in the US, we could not assess current treatment patterns for varicella infection from secondary databases. Hence, we utilized a case vignette approach for this study (8 vignettes). We did not use qualitative methodology for vignette selection and as such the vignettes may not comprehensively represent all varicella cases in the US. However, all vignettes were developed based upon expert clinical consultation and literature review of varicella cases. Unlike standard patient-provider interactions, in vignette studies, patients are unable to communicate their symptoms and providers are unable to ask probing questions. The smaller sample size does not imply generalizability to broader population. Like any other vignette survey, this study is subject to responder bias. Since the majority of respondents were licensed in more recent years, our ability to compare differences more robustly in diagnosis and treatment approaches by HCPs licensed in the pre- and post-vaccination era was limited. While year of licensure may be considered to be a reasonable proxy for provider experience with varicella, especially considering the sharp decline in varicella cases post vaccination, it is possible that providers licensed after 1996 may have gained experience with varicella cases in mini outbreaks in the country or through global experience. Lastly, our analyses are descriptive only, and the statistical significance of differences between the groups could not be assessed.

Various strategies can help improve the correct diagnosis and recognition of varicella infection as well as prevent inappropriate use of antibiotics and antivirals. Continuing education programs for HCPs on the recognition of varicella, its complications, high-risk groups for more severe disease, and appropriate management of cases (aimed at improving appropriate use of antibiotics and antivirals) could potentially lower healthcare resource utilization and the economic burden of varicella. Ensuring high vaccination coverage despite challenges by COVID-19 is critical.

Conclusions

In spite of the low incidence of varicella infections in the US, majority of the clinicians accurately diagnosed varicella infection. However, a considerable proportion of clinicians incorrectly recognized varicella infection with complications as well as recommended the inappropriate use of antimicrobial agents for management of varicella. Additional training may help HCPs better recognize and manage cases of varicella infection, while ensuring high rates of varicella vaccination is an important strategy to minimize unnecessary prescribing of antibiotic or antiviral therapies.

Survey.

Vignette information and survey file.

(DOCX)

Click here for additional data file.

19 Oct 2021

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Reviewer #1: In this paper, the authors describe a survey based study to evaluate the ability of pediatric physicians and advanced practice providers to recognize varicella in case vignettes. The hypothesis is that vaccination has made cases relatively rare and so cases may be missed when they present for medical attention. While I agree with the premise of the paper, I think there is much more information that needs to be provided before this paper should be published.

First, there is insufficient detail provided about how the survey was done. How were potential participants contacted (what listserv was used?), was this a regional or national group? was an incentive provided?

Second, the survey materials need to be provided as supplemental material for review prior to publication and also for review by any readers who want to access them.

Third, while age might be a very rough correlate, there was no question on whether a provider had previously diagnosed varicella before in their career. There are young people who have worked globally or helped care for those in mini-outbreaks in the US who have good experience with varicella patients. Since this cannot be done, it should be included as a limitation in the discussion.

The introduction does not have to provide the entire background of varicella. It could be streamlined significantly to offer enough detail to justify the study.

I am not sure the figures really offer any additional value to the reader.

Reviewer #2: Overall, I think it was a nicely done study looking at an important questions. I found the methods a little weak in how the vignettes, their definitions, and management plans were chosen. The results have so many numbers that it is difficult to pull out the important findings while reading. I think much of this results from whether the denominator is the providers, the vignettes, or the treatment options – as this changes throughout the paper -- it is difficult to go back and forth between these.

Intro –page 3, it would be useful to have some case numbers so that the reader could appreciate the absolute reductions along with the percentage drops – at least for conditions with appreciable morbidity (ie hospitalizations, pneumonia, encephalitis)

Is there a more recent case estimate than 2014?

It would be useful to know if any specific qualitative methodology helped to guideline the number/section of cases. Why 9:1 – that seem overly obvious.

Page 6. I would state that the removed varicella case was excluded from table 1.

Did a lot of people struggle with vignette #7? I would think that the correct answer would be hospitalization and antivirals +/- antibiotics for a child with a severe complication of VZV and underlying lung disease.

Table 3. I think should it be NP or APP rather than nurse?

Page 12. What reference are you using to define complicated vs uncomplicated VZV? #4 is really challenging as in many infectious disease states (ie, complicated UTI or complicated Staph aureus bacteremia) the “complicated” can be defined by EITHER the disease state OR the host being complicated. It is easy in #4 to see how the respondents may have considered a patient on an undefined amount of steroids to be an immunocompromised host and therefore “complicated” even if the presentation itself was not complicated. The fact that >50% called this case complicated suggest that the definitions chosen by the authors may not reflect what is considered complicated in clinical practice.

The following phrase is unclear “Among those who did not recognize varicella infection correctly across all vignettes (n=254),” as there were only 153 respondents. I think this means among those vignettes answered incorrectly? 153*8=1224; 254/1224=0.2 (20% or 254 incidents where varicella was incorrectly identified)

Although the table 4 says only 970 case (79.2%) of cases were correctly identified as varicella.

Lots of numbers are reported but there are really too many to take in.

The most interesting finding is that 20% of varicella cases were missed and 40% of complicated cases were misdiagnosed (if I interpreted this correctly).

This sentence is not clear “Across all uncomplicated vignettes, respondents licensed in the pre-vaccination era were more likely to recognize the case as varicella (94.6%) compared to those licensed in later years (83.3%).” Maybe move the ALL? “Across –all- uncomplicated vignettes, respondents licensed in the pre-vaccination era were more likely to recognize ALL cases as varicella (94.6%) compared to those licensed in later years (83.3%).

So <1996, 5% of uncomplicated cases and 29% of uncomplicated cases were misdiagnosed.

>1996, 23% of uncomplicated cases and 41% of complicated cases were misdiagnosed.

The figures are missing critical information. How the percentages were calculated should be self-evidence when one looks at a figure rather than having to go back to the text to figure out what the authors were using to calculate the percentages. For example, looking at the figure 1b, it is difficult to know whether labs were offered every time and selected incorrectly 100% percent of those times or whether every respondent selected it incorrectly at least once.

Again, I think presenting the #/% missed diagnoses rather than the correct diagnoses would have a great impact on the reader.

Reviewer #3: This is an original, interesting, and useful study. I encourage the authors to pursue its publication because it has practical implications for developing communication messages for a disease that is vaccine-preventable. Having said that, I identified several issues during my review. As general comments, there are many inaccuracies in the introduction that need to be fixed, I had some concerns about the primary treatment recommendations for some of the vignettes that influence the results, some wording in the results that seem to indicate statistical significance although the authors report that they did not assess it. In general, I think it would be beneficial to work with an editor for the next revision.

Specific comments are below:

Intro

- 1st para, 2nd sentence: single dose was the routine recommendation for children but people age 13+ years were recommended 2 doses. What is indicated as “single dose vaccination for individuals 12 months of age and older” is not accurate as indicated above.

- 1st para, 4th sentence: I don’t have the 2015 edition of the Pink Book as the 2021 edition is now available online but what the authors indicate as % reduction in this sentence seems to be vaccine coverage. I am not aware of reports of incidence trends reported for these specific age-groups, 19-35 months and 13-17 years, these are the ages where vaccination status is routinely reported. Please check and revise.

- Ref 4: it’s a paper on neurologic complications of herpes zoster, I could not find anything about the 2-dose regimen for varicella vaccination. The appropriate ref is the 2007 MMWR with ACIP recommendations. In the same sentence the vaccine “suppresses cases of varicella” is unusual, better “prevents”. Ref 4 is also inaccurately cited at the end of the 3rd para for varicella complications which the article does not present.

- Ref 5: described trends in outbreaks and not in cases as the authors indicated. The appropriate ref here is Lopez MMWR 2016 (current ref 9).

- 2nd para, 1st sentence: coverage is reported above, no need to mention it here again. “annual incidence remains as 3.9/100,00 ….”, remains is misleading, this is really a low rate and as reported in ref 9 it was an 85% decline from 2006, with continuing decline over that interval. Ref 8: cannot tell what ref is this -- Prevention CfDCa. Chickenpox (Varicella): Monitoring the Impact of Varicella Vaccination 2018 [. The same for ref 10 although this ref has a link.

- 3rd para, 3rd sentence: CDC does not make recommendations for treatment. CDC website cites the American Academy of Pediatrics (AAP) recommendations. There is a link that goes to the recommendations for treatment where it is mentioned that AAP recommended. Please update the reference to the original source.

- Last para, 1st sentence: decline in varicella outbreaks was not mentioned before, the intro indicated reduction in cases, should either add “cases” or mention only cases. I think cases are more relevant than outbreaks. “several decades” it’s really 2.5 decades.

- Ref 18: I was not able to find this reference online. The closest I came was a discussion with 2 experts about covid vaccines for children. Can the authors provide the link? Also, there are several articles published that show a show decline in vaccination rates among children during covid, suggest adding a peer-reviewed publication here. Same for the citation in the results.

Methods

- First paragraph: “The vignettes had a variety of uncomplicated and complicated presentations “, the vignettes do not have complications, maybe they presented or described, please edit. Also use of complicated and uncomplicated as adjectives vs varicella presentations with complications and without complications.

- Vignettes – Recommendations: unclear what “+/- catch-up vaccines” means? Is it that it can be recommended or not, and assessment should be based on what? Is this varicella vaccine or other vaccines? An acute disease is a precaution for vaccination. Vaccination is not indicated on vignettes 6 and 8, how were these patients different from the others for which vaccination is appropriate management?

- Vignette 7: what is “lung problems“? I would think that antivirals are appropriate for this child given varicella with complications (pneumonia), pulmonary problems, and hospitalization.

- Vignette 8: why antivirals are not considered appropriate for this case? It’s a 14-year-old and per the Red Book -- Oral acyclovir or valacyclovir should be considered for otherwise healthy people at increased risk of moderate to severe varicella, such as unvaccinated people older than 12 years, ….. How are patients on vignette 8 (antivirals not recommended) and 6 (antivirals recommended) different? Both are older than 12 and have varicella; exposure should not matter in this case as they are both older than 12. Red Book does indicate that “some experts recommend use of oral acyclovir or valacyclovir for secondary household cases …”, exposure does not indicate if it was household but even though the 14-year-old would be recommended for antivirals based on age.

Results

- First paragraph: “of these female respondents, 65.6% were licensed in the post-vaccination era.” Is this detail important, info is also in the table. Recommend deleting from text.

- Table 3. Row on Year of licensure is not needed it the table. It is reported in the text and having it in the table does not add anything for the reader.

- “more likely”, “less likely” mean statistical significance. They are used several times in the results, please provide p values or reword.

- Page 12, 1st para: use of “complicated cases” and “uncomplicated cases” makes the reading difficult here. Usually a “complicated case” is a difficult case and the expression should not be used as a substitute for “a case with complications”, at least not in the written literature. The authors used that wording throughout the article. “a complicated varicella infection with Staphylococcus aureus infection” vs. varicella complicated with Staph aureus infection.

- Page 12, 2nd para: “Across all uncomplicated vignettes”, the vignettes cannot be complicated please reword.

- Page 13, 2nd para: Lab tests - unclear what lab tests are these. I think lab test to confirm varicella is appropriate; also, for cases with complications lab tests would be appropriate. The authors indicate that “all were unnecessary”.

Discussion

- 2nd para: maybe para on antibiotic resistance can be moved later, the contribution of varicella would likely be small in the US because varicella is rare now, most cases occur in vaccinated patients and are mild, ¾ of recommendations were correctly made.

- Page 15, 2nd para: message of the last sentence is unclear and possibly inaccurate - If only a small fraction of all cases of varicella lead to hospitalization (e.g., 1% of cases leading to 5000 hospitalizations), this could lead to substantial costs to the health care system ranging from $20.7m to $110.6m. 1) The number of hospitalizations is high, in the prevaccine era an average of 10,500 hospitalizations occurred (Galil, PIDJ 2002) and they declined 93% by 2012 (Leung JPIDS 2015); 2) It seems that the sentence is in the context of hospitalizations due to incorrect recommendations for hospitalization, do the authors imply that 5,000 unnecessary hospitalizations would occur? 3) Unclear what the timeline of the $ estimate is – annual or over how many years. Not sure the authors have enough data to estimate unnecessary hospitalizations based on their study.

- Page 15, last line: seems a little offensive to indicate that clinicians licensed before 1995 are more seasoned clinicians compared to HCP’s licensed after 1995, do the authors imply that they are better clinicians?

**********

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Submitted filename: Review PONE-D-21-13847.docx

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3 Mar 2022

Review Comments to the Author & Responses

Thank you to all 3 reviewers for taking time to review the paper thoroughly and providing such insightful comments. Please see our responses below. We hope that we have addressed them to your satisfaction.

Best regards,

Authors

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Reviewer #1:

In this paper, the authors describe a survey-based study to evaluate the ability of pediatric physicians and advanced practice providers to recognize varicella in case vignettes. The hypothesis is that vaccination has made cases relatively rare and so cases may be missed when they present for medical attention. While I agree with the premise of the paper, I think there is much more information that needs to be provided before this paper should be published.

1) First, there is insufficient detail provided about how the survey was done. How were potential participants contacted (what listserv was used?), was this a regional or national group? was an incentive provided?

Response: Thank you for your comment. We have added details in the Methods section regarding the inclusion criteria, recruitment, and honoraria. The text now reads as follows, “HCPs were recruited by a survey vendor specializing in health care provider research with physicians and nurses from their existing panel of healthcare professionals (HCPs) across the United States. Respondents were invited via email to take part in the survey. Inclusion criteria included: either a board-certified physician in pediatrics/ family medicine/ Internal Medicine specialties treating at least 100 pediatric patients per month or a licensed nurse practitioner; currently practicing in the United States with ≥ 50% time spent in a clinical setting; English proficiency; and consent to participate. The survey was administered through an on-line portal. All participants received a modest incentive for their participation and were blinded to the study sponsors. Anonymized respondent data was delivered for analysis to prevent responses being linked directly to individual providers.”

2) Second, the survey materials need to be provided as supplemental material for review prior to publication and also for review by any readers who want to access them.

Response: We have included a copy of the survey in the supplement.

3) Third, while age might be a very rough correlate, there was no question on whether a provider had previously diagnosed varicella before in their career. There are young people who have worked globally or helped care for those in mini-outbreaks in the US who have good experience with varicella patients. Since this cannot be done, it should be included as a limitation in the discussion.

Response: Thank you for your valuable feedback. We wanted to prevent introduction of any bias by specifically asking about varicella and use of post-1996 licensure was an approximate proxy to reflect that physicians would see fewer varicella cases with each year post introduction of varicella vaccination. This has been now addressed in the discussion section as a limitation as follows:

“While year of licensure may be considered to be a reasonable proxy for provider experience with varicella, especially considering the sharp decline in varicella cases post vaccination, it is possible that providers licensed after 1996 may have gained experience with varicella cases in mini outbreaks in the country or through global experience. Lastly, our analyses are descriptive only, and the statistical significance of differences between the groups could not be assessed.”

4) The introduction does not have to provide the entire background of varicella. It could be streamlined significantly to offer enough detail to justify the study.

Response: Thank you. We have streamlined content throughout the background section of the manuscript as advised.

5) I am not sure the figures really offer any additional value to the reader.

Response: Thank you. We have removed the 2 figures. In addition, in response to other comments received, we have focused the results on the treatment options to the incorrect usage of antibiotic and antiviral and provided the data in the text.

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Reviewer #2

Overall, I think it was a nicely done study looking at an important question. I found the methods a little weak in how the vignettes, their definitions, and management plans were chosen. The results have so many numbers that it is difficult to pull out the important findings while reading. I think much of this results from whether the denominator is the providers, the vignettes, or the treatment options – as this changes throughout the paper -- it is difficult to go back and forth between these.

Response: Thank you for your valuable feedback. We have streamlined the results, with focus on varicella diagnosis and treatment. Data on the correct diagnosis in the text; with more details for provided in the table 4. Also, as regards the treatment options, we have restricted the scope of the paper to the antibiotic and antiviral usage. Additionally, we have added more details on the vignette’s selection process in the methods and clarification of the numbers/denominators as footnote s to Table 1 and 4.

1) Intro –page 3, it would be useful to have some case numbers so that the reader could appreciate the absolute reductions along with the percentage drops – at least for conditions with appreciable morbidity (i.e. hospitalizations, pneumonia, encephalitis)

Response: Thank you. We have added the absolute reductions as follows to better capture the impact. “Fifteen years of vaccination (1996 to 2010) allowed the US to demonstrate a dramatic decrease in burden of disease with only 20 annual deaths (90% decrease compared to pre-vaccine era), 1,700 hospitalizations (84% decrease) related to varicella reported in 2010 (1). It is estimated that the varicella vaccination program saves $373 million in direct cost and $1.598 billion in societal costs, annually in the US. (3)”

We restricted the reported impact to number of cases, hospitalizations, and mortality, but did not go into details for specific complications due to scarcity of data and our efforts to streamline the introduction in response to another reviewer comment.

2) Is there a more recent case estimate than 2014?

Response: This statement has been deleted to tighten the background section.

3) It would be useful to know if any specific qualitative methodology helped to guideline the number/section of cases. Why 9:1 – that seem overly obvious.

Response: We did not use qualitative methodology for vignette selection and this has been added as a part of limitation in the discussion section as follows, “We did not use qualitative methodology for vignette selection and as such the vignettes may not comprehensively represent all varicella cases in the US. However, all vignettes were developed based upon expert clinical consultation and literature review of varicella cases.” However, the primary objective of this study was to assess the ability to diagnosis varicella cases. We didn’t want to introduce respondent bias by informing them about varicella management upfront by disclosing this information.

Additional information has been added to the supplemental information as follows: “The first was a non-varicella case/vignette was included to gauge providers ability to distinguish between conditions with symptoms/presentations similar to varicella that need antibiotics. It had been deliberately added to avoid having all varicella cases. The other was a varicella case but removed after expert consultation since the choice of correct treatment was unclear due to the complexity of the case. Further clinical information, not provided in the vignettes, would have been necessary to make an appropriate treatment recommendation.”

4) Page 6. I would state that the removed varicella case was excluded from table 1.

Response: Thank you. We have edited the text to read “The final eight vignettes are shown in Table 1 and the survey provided in the supplement. Two of the 10 vignettes were excluded from the final analysis (and from Table 1 ; details are provided in the supplement) after consultation with 2 clinicians/ experts “ and added a footnote to the table. In addition, the supplement has more details on why the 2 cases were excluded. “

5) Did a lot of people struggle with vignette #7? I would think that the correct answer would be hospitalization and antivirals +/- antibiotics for a child with a severe complication of VZV and underlying lung disease.

Response: We have corrected a typo here. Apologies.

7 Healthy 6-year-old, respiratory sign/symptoms seen. 1-dose vaccination, no known exposure to varicella Varicella with

Complication (pneumonia) Antibiotics

Hospitalization

+/- Supportive care

We have added an explanation in the supplement as follows: “Similarly, for Vignettes#7 again, the 5-day history of rash in a previously healthy 6 year old child meant that the pulmonary complications were more likely secondary bacterial pneumonia rather than primary viral process(AAP reference). It would be most appropriate to hospitalize and start antibiotics. While some physicians might initiate antivirals for some children while evaluating for possible immunodeficiency, consensus for the appropriate treatment of most children would be hospitalization + antibiotics”

6) Table 3. I think should it be NP or APP rather than nurse?

Response: Thank you. We have corrected this information. The provider type in the table now reads “Nurse Practitioner.”

7) Page 12. What reference are you using to define complicated vs uncomplicated VZV? #4 is really challenging as in many infectious disease states (i.e., complicated UTI or complicated Staph aureus bacteremia) the “complicated” can be defined by EITHER the disease state OR the host being complicated. It is easy in #4 to see how the respondents may have considered a patient on an undefined amount of steroids to be an immunocompromised host and therefore “complicated” even if the presentation itself was not complicated. The fact that >50% called this case complicated suggest that the definitions chosen by the authors may not reflect what is considered complicated in clinical practice.

Response: We have updated the manuscript, so that “uncomplicated” and “complicated” varicella is correctly referred to as “varicella with and without complications”. In addition, we have added a statement in the Methods section stating that “Correct diagnosis (varicella with or without complications) and appropriate disease management was defined for each vignette using the American Academy of Pediatrics (AAP) Red Book, clinical infectious disease expert input, and literature.”

8) The following phrase is unclear “Among those who did not recognize varicella infection correctly across all vignettes (n=254),” as there were only 153 respondents. I think this means among those vignettes answered incorrectly? 153*8=1224; 254/1224=0.2 (20% or 254 incidents where varicella was incorrectly identified) Although the table 4 says only 970 case (79.2%) of cases were correctly identified as varicella.

Response: - Restated for clarity as follows: “Among the 254 responses where varicella infection was not correctly identified, bacterial infection, not otherwise specified (24.8%), “other” (20.1%), impetigo (19.3%), and hand, foot & mouth disease (12.2%) were the most common diagnoses selected.” Also, a footnote was added to table 4 “* N refers to total number of vignettes and not the number respondents. Thus, the total number of vignettes in the survey is 153 respondents*8 vignettes each =1224 vignettes. Of these, only the ones correctly diagnosed are reported here. There was no missing vignette for any respondent.”

9) Lots of numbers are reported but there are really too many to take in.

The most interesting finding is that 20% of varicella cases were missed and 40% of complicated cases were misdiagnosed (if I interpreted this correctly).

Response: We have streamlined the results, choosing to report the antibiotic and antiviral usage for treatment options rather than trying to report everything. Thus, we have deleted the figures

10) This sentence is not clear “Across all uncomplicated vignettes, respondents licensed in the pre-vaccination era were more likely to recognize the case as varicella (94.6%) compared to those licensed in later years (83.3%).” Maybe move the ALL? “Across –all- uncomplicated vignettes, respondents licensed in the pre-vaccination era were more likely to recognize ALL cases as varicella (94.6%) compared to those licensed in later years (83.3%).

Response: To aid in clarity, we have removed the term “all” from the sentence.

11) So <1996, 5% of uncomplicated cases and 29% of uncomplicated cases were misdiagnosed.>1996, 23% of uncomplicated cases and 41% of complicated cases were misdiagnosed.

Response: Thank you for the suggestion. We have incorporated the suggested language as “Those licensed in the pre-vaccination era were more likely to recognize varicella infection (88.8%) compared to those licensed in the post-vaccination era (77.1%). Among respondents who accurately recognized varicella infection, the majority (86.7%) accurately categorized the infection as uncomplicated or complicated. Respondents licensed in the pre-vaccination era correctly recognized complication status 87.4% of the time, similar to those licensed in the post-vaccination era (86.5%).”

12) The figures are missing critical information. How the percentages were calculated should be self-evidence when one looks at a figure rather than having to go back to the text to figure out what the authors were using to calculate the percentages. For example, looking at the figure 1b, it is difficult to know whether labs were offered every time and selected incorrectly 100% percent of those times or whether every respondent selected it incorrectly at least once.

Response: Thank you. We have deleted the 2 figures. In addition, in response to other comments received, we have focused the results regarding the treatment options to the incorrect usage of antibiotic and antiviral and provided the data in the text

13) Again, I think presenting the #/% missed diagnoses rather than the correct diagnoses would have a great impact on the reader.

Response: Thank you. We have reported the %missed diagnosis in the text as suggested in the comment above. We have kept the % correct diagnosis in the table 4 since the number of vignettes correctly diagnosed as varicella form the denominator for the % that is diagnosed correctly as complicated or not.

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Reviewer #3

This is an original, interesting, and useful study. I encourage the authors to pursue its publication because it has practical implications for developing communication messages for a disease that is vaccine-preventable. Having said that, I identified several issues during my review. As general comments, there are many inaccuracies in the introduction that need to be fixed, I had some concerns about the primary treatment recommendations for some of the vignettes that influence the results, some wording in the results that seem to indicate statistical significance although the authors report that they did not assess it. In general, I think it would be beneficial to work with an editor for the next revision. Specific comments are below:

RESPONSE: Thank you for your review and taking time for providing such insightful comments. We hope that we have addressed them satisfactorily below.

Intro:

1) 1st para, 2nd sentence: single dose was the routine recommendation for children but people age 13+ years were recommended 2 doses. What is indicated as “single dose vaccination for individuals 12 months of age and older” is not accurate as indicated above.

Response: Thank you. The sentence now has an updated reference for the 2007 ACIP CDC recommendations and reads as follows: “Introduction of the varicella vaccination program in 1995 was a major milestone in the fight against this disease, with the Advisory Committee on Immunization Practices (ACIP) recommending 1 dose for routine childhood varicella vaccination and catch-up for children up to 12 years and 2 vaccine doses for older susceptible persons at greater risk (≥ 13 years of age). (2) In 2006, ACIP expanded to a two-dose recommendation for all children and adolescents/adults without evidence of immunity.”

2) 1st para, 4th sentence: I don’t have the 2015 edition of the Pink Book as the 2021 edition is now available online but what the authors indicate as % reduction in this sentence seems to be vaccine coverage. I am not aware of reports of incidence trends reported for these specific age-groups, 19-35 months and 13-17 years, these are the ages where vaccination status is routinely reported. Please check and revise.

Response: Thank you. We have updated this to the more commonly available reference from the CDC infographic. The text was updated as” Fifteen years of vaccination (1996 to 2010) allowed the US to demonstrate a dramatic decrease in the annual burden of disease with 20 varicella related deaths (90% decrease compared to pre-vaccine era), 1,700 hospitalizations (84% decrease) and 350,000 varicella cases (92% decrease) in 2010 (1). It is estimated that the varicella vaccination program saves $373 million in direct cost and $1.598 billion in societal costs, annually in the US. (3)

3) Ref 4: it’s a paper on neurologic complications of herpes zoster, I could not find anything about the 2-dose regimen for varicella vaccination. The appropriate ref is the 2007 MMWR with ACIP recommendations. In the same sentence the vaccine “suppresses cases of varicella” is unusual, better “prevents”. Ref 4 is also inaccurately cited at the end of the 3rd para for varicella complications which the article does not present

Response: Thank you for noticing this error. The sentence now has an updated reference for the 2007 ACIP CDC recommendations and reads as follows: “Introduction of the varicella vaccination program in 1995 was a major milestone in the fight against this disease, with the Advisory Committee on Immunization Practices (ACIP) recommending 1 dose for routine childhood varicella vaccination and catch-up for children up to 12 years and 2 vaccine doses for older susceptible persons at greater risk (≥ 13 years of age). (2) In 2006, ACIP expanded the recommendation to two doses for all children, and adolescents/adults without evidence of immunity.”

4) Ref 5: described trends in outbreaks and not in cases as the authors indicated. The appropriate ref here is Lopez MMWR 2016 (current ref 9).

Response: The reference has been updated to the Lopez MMWR 2016 reference.

5) 2nd para, 1st sentence: coverage is reported above, no need to mention it here again. “annual incidence remains as 3.9/100,00 ….”, remains is misleading, this is really a low rate and as reported in ref 9 it was an 85% decline from 2006, with continuing decline over that interval. Ref 8: cannot tell what ref is this -- Prevention CfDCa. Chickenpox (Varicella): Monitoring the Impact of Varicella Vaccination 2018 [. The same for ref 10 although this ref has a link.

Response: We have removed this statement in order to streamline the introduction.

6) 3rd para, 3rd sentence: CDC does not make recommendations for treatment. CDC website cites the American Academy of Pediatrics (AAP) recommendations. There is a link that goes to the recommendations for treatment where it is mentioned that AAP recommended. Please update the reference to the original source.

Response: The sentence now reads as follows “The American Academy of Pediatrics (AAP) notes that antivirals are primarily recommended for use with populations at increased risk for complications, including immunocompromised individuals.” The citation now links to an AAP source directly.

7) Last para, 1st sentence: decline in varicella outbreaks was not mentioned before, the intro indicated reduction in cases, should either add “cases” or mention only cases. I think cases are more relevant than outbreaks. “several decades” it’s really 2.5 decades.

Response: The sentence now reads as follows: “Despite the high rate of vaccination and resulting steep decline in varicella cases over the past several decades, growing hesitancy to childhood vaccinations (10) and delays in vaccinations due to the current COVID-19 pandemic, raise concerns about a potential increase in vaccine preventable diseases, including varicella, in the coming years. (11)”

8) Ref 18: I was not able to find this reference online. The closest I came was a discussion with 2 experts about covid vaccines for children. Can the authors provide the link? Also, there are several articles published that show a show decline in vaccination rates among children during covid, suggest adding a peer-reviewed publication here. Same for the citation in the results.

Response: Thank you. We have added a journal reference for this in the introduction section and deleted the sentence from the Discussion section.

Methods:

9) First paragraph: “The vignettes had a variety of uncomplicated and complicated presentations “, the vignettes do not have complications, maybe they presented or described, please edit. Also use of complicated and uncomplicated as adjectives vs varicella presentations with complications and without complications.

Response: The sentence now reads as follows: “The vignettes varied in the age (1-15 years), health profiles, clinical presentations, childhood vaccination status, and presence of complications.”

10) Vignettes – Recommendations: unclear what “+/- catch-up vaccines” means? Is it that it can be recommended or not, and assessment should be based on what? Is this varicella vaccine or other vaccines? An acute disease is a precaution for vaccination. Vaccination is not indicated on vignettes 6 and 8, how were these patients different from the others for which vaccination is appropriate management?

RESPONSE: Since some of the vignettes did not have up-to date vaccination status, this referred to catching up the patient to ensure he is up to date with all vaccines, when possible. However, analyzing that was not within scope of this analysis.

11) Vignette 7: what is “lung problems“? I would think that antivirals are appropriate for this child given varicella with complications (pneumonia), pulmonary problems, and hospitalization.

Response: We apologize. Vignette 7 in table 1 was corrected to:

7 Healthy 6-year-old, respiratory sign/symptoms. 1-dose vaccination, no known exposure to varicella Varicella with

Complication (pneumonia) Antibiotics

+Hospitalization

+/- Supportive care

”We have also added an explanation in the supplement as follows to explain the reasoning behind the treatment pattern: …“AAP Red Book indicates that “Antiviral drugs have a limited window of opportunity to affect the outcome of VZV infection. In immunocompetent hosts, most virus replication has stopped by 72 hours after onset of rash; the duration of replication may be extended in immunocompromised hosts……Similarly, for Vignettes#7 again, the 5-day history of rash in a previously healthy 6 year old child meant that the pulmonary complications were more likely secondary bacterial pneumonia rather than primary viral process(AAP reference). It would be most appropriate to hospitalize and start antibiotics. While some physicians may prefer to start antivirals just in case while working the child up for immunodeficiency, so we feel that the appropriate treatment would be hospitalization + antibiotics”

A copy of the survey in the supplement has bene provided where the description for this vignette states, “A 6-year-old previously healthy child presented with a 5-day history of pruritic rash, which consisted of approximately 350 vesicular lesions, loss of appetite, fatigue, and chest pain. The patient developed a high-grade fever and cough 4 days after the onset of rash symptoms. On examination, the child’s temperature was 102° F. The child was unable to tolerate oral intake, had a respiratory rate < 50/minute, and decreased oxygen saturation (65%). Auscultation of lungs revealed crackles in lower lobes of lungs. Growth and development were otherwise normal. All of the child’s immunizations were not up to date according to the recommended US child vaccination schedule: the child missed the second doses of the MMR and varicella vaccines. The child had no known exposure to hand foot and mouth disease, scabies, or poison ivy/oak ”

12) Vignette 8: why antivirals are not considered appropriate for this case? It’s a 14-year-old and per the Red Book -- Oral acyclovir or valacyclovir should be considered for otherwise healthy people at increased risk of moderate to severe varicella, such as unvaccinated people older than 12 years, ….. How are patients on vignette 8 (antivirals not recommended) and 6 (antivirals recommended) different? Both are older than 12 and have varicella; exposure should not matter in this case as they are both older than 12. Red Book does indicate that “some experts recommend use of oral acyclovir or valacyclovir for secondary household cases …”, exposure does not indicate if it was household but even though the 14-year-old would be recommended for antivirals based on age.

Response: Thank you. We have now addressed this in the supplement as follows: For vignette#8, after expert consultation, the use of antivirals was deemed unnecessary based on the duration of time (5 days rash) & description of an immunocompetent individual. The 5 days vs 3 days was the critical difference since the AAP Red Book indicates that “Antiviral drugs have a limited window of opportunity to affect the outcome of VZV infection. In immunocompetent hosts, most virus replication has stopped by 72 hours after onset of rash; the duration of replication may be extended in immunocompromised hosts” (AAP reference)

Results

13) First paragraph: “of these female respondents, 65.6% were licensed in the post-vaccination era.” Is this detail important, info is also in the table. Recommend deleting from text.

Response: Agree. We have removed this as suggested.

14) Table 3. Row on Year of licensure is not needed it the table. It is reported in the text and having it in the table does not add anything for the reader.

Response: This row has been removed as suggested.

15) “more likely”, “less likely” mean statistical significance. They are used several times in the results, please provide p values or reword.

Response: Instances where “more likely” and “less likely” were used in the paper have been removed and replaced with more specific language, such as “prescribed more often.”

16) Page 12, 1st para: use of “complicated cases” and “uncomplicated cases” makes the reading difficult here. Usually a “complicated case” is a difficult case and the expression should not be used as a substitute for “a case with complications”, at least not in the written literature. The authors used that wording throughout the article. “a complicated varicella infection with Staphylococcus aureus infection” vs. varicella complicated with Staph aureus infection.

Response: Thank you. We have revised the manuscript accordingly in both the text and tables. We hope that it meets your satisfaction.

17) Page 12, 2nd para: “Across all uncomplicated vignettes”, the vignettes cannot be complicated please reword.

Response: Thank you. The statement was deleted as part of the streamlining the results. But the manuscript was revised as per he suggested advice regarding correct use of the terms.

18) Page 13, 2nd para: Lab tests - unclear what lab tests are these. I think lab test to confirm varicella is appropriate; also, for cases with complications lab tests would be appropriate. The authors indicate that “all were unnecessary”.

Response: We revised the scope of the reported treatment to antiviral and antibiotics only.

Discussion

19) 2nd para: maybe para on antibiotic resistance can be moved later, the contribution of varicella would likely be small in the US because varicella is rare now, most cases occur in vaccinated patients and are mild, ¾ of recommendations were correctly made.

Response: The second and third paragraphs have been swapped.

20) Page 15, 2nd para: message of the last sentence is unclear and possibly inaccurate - If only a small fraction of all cases of varicella lead to hospitalization (e.g., 1% of cases leading to 5000 hospitalizations), this could lead to substantial costs to the health care system ranging from $20.7m to $110.6m. 1) The number of hospitalizations is high, in the prevaccine era an average of 10,500 hospitalizations occurred (Galil, PIDJ 2002) and they declined 93% by 2012 (Leung JPIDS 2015); 2) It seems that the sentence is in the context of hospitalizations due to incorrect recommendations for hospitalization, do the authors imply that 5,000 unnecessary hospitalizations would occur? 3) Unclear what the timeline of the $ estimate is – annual or over how many years. Not sure the authors have enough data to estimate unnecessary hospitalizations based on their study.

Response: Thank you. We have deleted this statement to minimize confusion and streamline the discussion.

21) Page 15, last line: seems a little offensive to indicate that clinicians licensed before 1995 are more seasoned clinicians compared to HCP’s licensed after 1995, do the authors imply that they are better clinicians?

Response: We apologize for the verbatim. We didn’t intend to imply that. This sentence has been removed.

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Submitted filename: Response to Reviewers.docx

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26 Apr 2022

23 May 2022

Review Comments to the Author & Responses

Thank you to the reviewers for taking time to review the paper thoroughly and providing such insightful comments. Please see our responses below. We hope that we have addressed them to your satisfaction.

Best regards,

Authors

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Reviewer #2:

1. Table 4 Vignette 7 – the word pneumonia is missing

Response: The word “pneumonia” has been added to the box in column one.

2. Table 5 – should include the baseline comparison of what is the guideline recommended antiviral/antibiotic use

Response: The table has been replaced with a new table that includes baseline comparisons for full context.

3. Second to last sentence of results – remove word recommendations

Response: The word “recommendations” has been removed from the relevant sentence.

4. Last sentence of results – rewrite sentence to avoid “less incorrectly” which is confusing

Response: The sentence has been reworded and now reads as follows: “Conversely, antivirals were incorrectly recommended less often by HCPs licensed earlier (63.9%) compared to those licensed later (72.1%).”

5. Third sentence of discussion needs to be rewritten for clarity

Response: The sentence has been reworded and now reads as follows: “However, vaccine hesitancy (15) and delays in routine pediatric vaccination due to COVID-19 (11) has impacted the vaccination patterns and coverage rates. It is important to accurately diagnose and manage pediatric infectious diseases such as varicella.”

Submitted filename: Response to reviewers 5.20.22.docx

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25 May 2022

Recognition & Management of Varicella Infections and Accuracy of Antimicrobial Recommendations: Case vignettes study in the US

PONE-D-21-13847R2

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Thank for addressing all reviewer comments.

Reviewers' comments:

1 Jun 2022

PONE-D-21-13847R2

Recognition & Management of Varicella Infections and Accuracy of Antimicrobial Recommendations: Case vignettes study in the US

Dear Dr. Harley:

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