Risk and outcome of COVID-19 infection in sarcoidosis patients: results of a self-reporting questionnaire

Abstract

Background:

It has been suggested that sarcoidosis patients, especially those on immunosuppressive medications, are at increased risk for COVID-19 infection and more severe disease.

Methods:

A questionnaire was developed in four languages (English, Dutch, Italian, and Spanish). The questionnaire queried whether patients had been infected with COVID-19 and outcome of the infection. Risk factors for COVID-19 infection were collected.

Results:

A total of 5200 sarcoidosis patients completed the questionnaire with 116 (2.23%) reporting infection and 18 (15.8%) required hospitalization. Increased hazard ratio (HR) for COVID-19 infection were seen for those with a COVID-19 infected roommate (HR=27.44, p<0.0001), health care provider (HR=2.4, p=0.0001), pulmonary sarcoidosis (HR=2.48, p=0.001), neurosarcoidosis (HR=2.02, p<0.01), or rituximab treatment (HR=5.40, p<0.0001). A higher rate of hospitalization was found for those with underlying heart disease (HR=3.19 (1.297-7.855), p<0.02). No other feature including race, other immunosuppressive agent, age, or underlying condition was associated with a significant increased risk for infection or more severe disease.

Conclusion:

The overall rate of COVID-19 was 2.23%, suggesting an increased rate of COVID-19 infection. However, when an analysis of the questionnaires of sarcoidosis and non-sarcoidosis patients was performed in one localized area over this time period, the rate of COVID-19 infection was similar in both groups. Sarcoidosis patients who cohabitated with COVID-19 infected individuals, worked in health care, had pulmonary or neurologic sarcoidosis, or were treated with rituximab had an increased risk for COVID-19 infection. No significant increased risk for hospitalization could be identified based on age, race, gender or any specific immunosuppressive treatment. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (4): e2020009)

Supplement S-1 Questionnaires

UC/AMC and FSR questionnaire

COVID-19 questionnaire

1. By completing this questionnaire, you are agreeing to have this data shared with others and understand that a summary of data may be published. Do you agree?

   • Yes
   • No
2. Have you been infected with COVID-19 (corona virus)?

   • Yes
   • No

     1. If yes, what was outcome (check all that apply)
   • Treated only at home
   • I was hospitalized but I did not go to an intensive care area
   • Treated at any time in an intensive care area
   • At any time on a ventilator (breathing machine)
3. Have any people who live in the same house/apartment as me been diagnosed with COVID-19 (corona virus)?

   • Yes
   • No
4. Are you a health care provider?

   • Yes
   • No
5. I have the following medical conditions (check all that apply)

   • Sarcoidosis

     1. If sarcoidosis, how many years have you had sarcoidosis: ________________
   • COPD/Asthma
   • Cancer
   • Diabetes
   • Heart disease
   • Hypertension
   • Other

6. Your age: ________________

7. Your race (check all that apply)

   • Black
   • White
   • Asian
   • Other
8. Sex:

   • Female
   • Male

9. I live in the following state (if United States) or country (if not USA): _______________

   IF I HAVE SARCOIDOSIS, PLEASE ANSWER THE FOLLOWING FIVE QUESTIONS

10. I have sarcoidosis in the following areas of my body (check all that apply)

    • Lung
    • Heart
    • Brain
    • Other
11. I have been treated in past 3 months for sarcoidosis with (check all that apply)

    • Prednisone/prednisolone

      1. If yes, current daily dose of prednisone/prednisolone __________
    • Methotrexate/Azathioprine (Imuran)/Mycophenolate (Cellcept)/Leflunomide(Arava)
    • Infliximab (Remicade/Renflexis/Inflectra)/Adalimumab(Humira)
    • Hydroxychloroquine(Plaquenil)/Chloroquine
    • Rituximab (Rituxan)
    • Other chemotherapy
    • Other
12. In the past, have you been treated for sarcoidosis with (check all that apply)?

    • Prednisone/prednisolone/decadron
    • Methotrexate/Azathioprine (Imuran)/Mycophenolate (Cellcept)/Leflunomide(Arava)
    • Infliximab (Remicade/Renflexis/Inflectra)/Adalimumab(Humira)
    • Hydroxychloroquine(Plaquenil)/Chloroquine
    • Rituximab (Rituxan)
    • Other chemotherapy
    • Other
13. This is the initial questionnaire?

    • Yes
    • No
14. If this is the initial questionnaire, do you agree to being contacted in 3-6 months to complete this questionnaire a second time?

    • Yes
    • No

Supplement S-2

Dutch Questionnaire

COVID-19 / Corona vragenlijst voor sarcoïdosepatiënten

Patient information:

In korte tijd heeft COVID-19 wereldwijd toegeslagen en het leven veranderd. Het heeft tot veel onzekerheden geleid.

Bent u sarcoïdosepatiënt dan wordt u gevraagd deze survey in te vullen. Met nadruk willen we erop wijzen dat ook wanneer u geen COVID-19 infectie heeft gehad, u toch wordt verzocht de vragenlijst in te vullen.

Met uw hulp kunnen we dan trachten betrouwbare cijfers ook uit Nederland te verzamelen.

Betreffende sarcoïdose en COVID-19 kwamen allerlei vragen naar voren:

• Heeft een sarcoïdosepatiënt een hoger risico op het krijgen van een COVID-19 infectie?

• Als een sarcoïdosepatiënt geïnfecteerd raakt, heeft hij of zij dan een ernstiger beloop?

• Hebben sarcoïdosepatiënten die prednison of andere immunosuppressiva (medicijnen die het afweersysteem onderdrukken) gebruiken een hoger risico op het geïnfecteerd raken met COVID-19?

• Beschermt het gebruik van hydroxychloroquine een sarcoïdosepatiënt tegen COVID-19?

• Heeft geslacht, ras, gewicht, of leeftijd invloed op het risico of de uitkomst van COVID-19?

Om deze vragen te kunnen beantwoorden zijn de Foundation for Sarcoidosis Research (FSR) en de Universiteit van Cincinnati, met als hoofdonderzoeker prof. Robert Baughman, een survey onder sarcoïdosepatiënten gestart in de USA. Om hierover ook een indruk te krijgen in de rest van de wereld zijn diverse landen benaderd om ook deze vragenlijst onder sarcoïdosepatiënten uit te zetten, waaronder Nederland. Deze vragenlijst wordt in Nederland op verzoek van de initiatiefnemers verspreid door de ild care foundation in samenwerking met Sarcoidose.nl.

Door deze vragenlijst in te vullen, stemt u ermee in dat de gegevens anoniem verwerkt worden. Een samenvatting van het onderzoek zal, op basis van anonieme gegevens, gepubliceerd worden.

Bij voorbaat hartelijk dank voor uw medewerking!

1. Bent u besmet (geweest) met COVID-19 (coronavirus)?

   • Ja
   • Nee
   • Weet het niet zeker, ben niet getest, maar heb wel symptomen (gehad)
2. Zo ja, wat was er nodig voor de behandeling? (vink aan wat van toepassing is) :

   • Kon thuis worden behandeld
   • Ben opgenomen geweest in een ziekenhuis, maar ben niet op de intensive care verpleegd
   • Ben opgenomen geweest op een intensive care afdeling
   • Ben beademd met een ventilator (beademingsmachine)
   • Niet van toepassing, geen COVID-19 gehad
3. Zijn er mensen die in hetzelfde huis/ appartement wonen als u, die besmet zijn geweest met COVID-19 (corona virus)?

   • Ja
   • Nee
4. Bent u een zorgverlener?

   • Ja
   • Nee

5. Hoe lang heeft u al sarcoïdose? (jaren, maanden)

6. Ik heb sarcoïdose in de volgende organen/delen van mijn lichaam: (vink aan wat van toepassing is, meerdere keuzes mogelijk)

   • Longen
   • Hart
   • Hersenen / zenuwstelsel
   • Anders, nl.:
7. Ik heb naast sarcoïdose ook de volgende medische aandoeningen (vul in wat van toepassing is)

   • geen andere aandoeningen
   • Kanker
   • Diabetes
   • Hart-vaataandoening
   • Hartfalen
   • Hypertensie / hoge bloeddruk
   • COPD
   • Astma
   • Andere aandoening:
8. Nadat ik COVID-19 heb gehad, zijn mijn klachten:

   • verergerd
   • minder geworden dan voorheen
   • hetzelfde gebleven
   • niet van toepassing, heb geen COVID-19 gehad.

9. Wat is u leeftijd? (jaren)

10. Wat is uw gewicht? (in kg)

11. Wat is uw lengte (in cm)

12. Wat is uw geslacht?

    • Vrouw
    • Man
    • gender neutraal
13. Wat is uw etniciteit?

    • Kaukasisch / wit
    • Negroide / Afro Amerikaans / zwart
    • Aziatisch
    • Anders, nl./:
14. Ik woon in (land) :

    • Nederland
    • België
    • Anders, nl.:
15. Bent u in de afgelopen 3 maanden behandeld voor sarcoïdose met: (vink aan wat van toepassing is, meerdere antwoorden mogelijk)

    • Prednison/prednisolon (graag de huidige dagelijkse dosis onderaan deze vraag invullen)
    • Methotrexaat
    • Azathioprine (Imuran)
    • Cellcept (Mycophenolaat)
    • Leflunomide (Arava)
    • Infliximab (Remicade/Renflexis/Inflectra)
    • Adalimumab (Humira)
    • Hydroxychloroquine (Plaquenil)/Chloroquine
    • Rituximab (Rituxan)
    • Andere immunotherapie
    • Andere behandelwijze
    • Geen medicatie of behandeling

    Dosering Prednison per dag (in mg):

    Bewerken Opties

    Bewerken Opties Logica Verplaatsen Kopiëren Verwijderen

16. Bent U In het verleden behandeld voor sarcoïdose met (vink aan wat van toepassing is)?

    • Prednison/prednisolon (graag de huidige dagelijkse dosis onderaan deze vraag invullen)
    • Methotrexaat
    • Azathioprine (Imuran)
    • Cellcept (Mycophenolaat)
    • Leflunomide (Arava)
    • Infliximab (Remicade/Renflexis/Inflectra)
    • Adalimumab (Humira)
    • Hydroxychloroquine (Plaquenil)/Chloroquine
    • Rituximab (Rituxan)
    • Andere immunotherapie
    • Andere behandelwijze
    • Geen medicatie of behandeling

    Dosering Prednison per dag (in mg):

    Bewerken Opties

    Nieuwe vraag

    Hartelijk dank voor uw medewerking!

Supplement S-3

Italian Questionnaire

The following questionnaire was created using GOOGLE FORMS.

For further infos, please visit https://www.google.com/intl/en-US/forms/about/

Every single answer or group of answers generate both visual data and an excel file with the sum of all data.

Dati epidemiologici

• 1. Completando questo questionario, si autorizza alla condivisione dei dati qui raccolti e si dà il benestare alla eventuale pubblicazione anonima dei dati stessi. Dai il tuo consenso?

  • Si
  • No
• 2. Età

  • Scegli (choose - dropdown menu)
• 3. Sesso

  • Maschile
  • Femminile
  • Preferisco non rispondere
• 4. Etnia

  • Caucasica (prevalentemente europea)
  • Afro-americana
  • Asiatica
  • Preferisco non rispondere
• 5. Sei un operatore sanitario?

  • Si
  • No
• 6. In quale regione vivi?

  • Scegli (choose - dropdown menu)

Covid-19 e Sarcoidosi

• 7. Sei stata/o contagiata/o dal COVID-19 (coronavirus)?

  • No
• 7a. Se si, quale esito ha avuto (segnare tutte opzioni pertinenti)

  • Trattamento esclusivamente a casa
  • Ricovero in ospedale ma non in area intensiva
  • Curato in terapia intensiva
  • Curato con ventilazione assistita
• 8. Ci sono state persone conviventi nella tua abitazione che sono state contagíate dal COVID-19 (coronavirus)?

  • Si
  • No
• 9. Attualmente soffri di una o più delle seguenti patologie? (segnare tutte le patologie in essere)

  • Sarcoidosi
  • BPCO/Asma
  • Cancro
  • Diabete
  • Ipertensione
  • Altro
• 9a. Se hai segnato la sarcoidosi, da quanti anni ne soffri? (non si intende da che età, ma gli anni di malattia)

  • Scegli (choose - dropdown menu)
• 10. Quale area del tuo corpo è interessata dalla Sarcoidosi? (specificare quale o quali)

  • Polmoni
  • Cuore
  • Sistema nervoso Altro
• 11. Negli ultimi 3 mesi ti sei stato sottoposto ad una o più d’una delle seguenti terapie? (indica le voci pertinenti)

  • Prednisone/Prednisolone (farmaci cortisonici)
  • Metotrexato/Azatriopina/Micofenolato/Leflunomide
  • Infliximab/Adalimumab
  • Idrossiclorochina/Clorochina (Plaquenil)
  • Rituximab
  • Altre chemioterapie
  • Nessuna terapia
• 11a. Se hai assunto prednisone/prednisolone (farmaci cortisonici), qual è stata la dose giornaliera (quantificata in mg)?

  • Scegli (choose - dropdown menu)
• 11a.2 Se alla domanda precedente hai indicato ’altro’ scrivi qui la dose giornaliera di cortisonici (quantificata in mg)

  • ______________ risposta aperta (open response)
• 11b. Se hai assunto Idrossiclorochina/Clorochina (Plaquenil), qual è stata la dose giornaliera (quantificata in mg)? (this question is only in the Italian Survey)

  • Scegli (choose - dropdown menu)
• 11b.2 Se alla domanda precedente hai indicato ’altro’ scrivi qui la dose giornaliera di Idrossiclorochina/Clorochina(quantificata in mg)

  • ___________ risposta aperta (open response)
• 12. In passato sei stato sottoposto ad una o più d’una delle seguenti terapie? (indica le voci pertinenti)

  • Prednisone/Prednisolone (farmaci cortisonici)
  • Metotrexato/Azatriopina/Micofenolato/Leflunomide
  • Infliximab/Adalimumab
  • Idrossiclorochina/Clorochina (Plaquenil)
  • Rituximab
  • Altre chemioterapie
  • Nessuna terapia
• 13. Una versione precedente di questo questionario è già stata condotta durante il mese di aprile. Hai già compilato il 1 ° questionario di apnle?

  • I Si
  • I No

Supplement S-4

Spanish Questionnaire

Cuestionario COVID-19

• 1- Al completar este cuestionario, acepta compartir estos datos con otros y comprende que se puede publicar un resumen de los datos. ¿Está de acuerdo?

  • SÍ
  • NO
• 2- ¿Ha sido infectado con COVID-19 (coronavirus)?

  • SÍ
  • NO

    1. En caso afirmativo, cuál fue el resultado (marque todos los que correspondan)
  • Tratado solo en casa
  • Fui hospitalizado pero no fui a un área de cuidados intensivos
  • Tratado en cualquier momento en un área de cuidados intensivos
  • En cualquier momento en un ventilador (máquina de respiración)
• 3- ¿Alguna de las personas que viven en la misma casa / departamento que yo ha sido diagnosticada con COVID-19 (coronavirus)?

  • SÍ
  • NO
• 4- ¿Es usted un proveedor de atención médica?

  • SÍ
  • NO
  • Sarcoidosis Si tiene sarcoidosis, ¿cuántos años ha tenido sarcoidosis? ____________
  • EPOC / Asma
  • Cáncer
  • Diabetes
  • Enfermedad del corazón
  • Hipertensión
  • Otro

• 6- Edad:

• 7- Origen étnico

  • Negro
  • Blanco
  • Asiático
  • Otros
  • Prefiero no responder
  • Masculino
  • Femenino
  • Prefiero no responder

• 9- Vivo en el siguiente estado/país ____________

• 10- Este es el cuestionario inicial?

  • Si
  • No

SI TIENE SARCOIDOSIS, RESPONDA LAS SIGUIENTES CINCO PREGUNTAS

• 11- Tengo sarcoidosis en las siguientes áreas de mi cuerpo (marque todas las que correspondan)

  • Pulmón
  • Corazón
  • Cerebro
  • Otro
  • corresponda)
  • Prednisona / prednisolona

    1. En caso afirmativo, la dosis diaria actual de prednisona / prednisolona
  • Metotrexato / Azatioprina (Imuran) / Micofenolato (Cellcept) / Leflunomida (Arava)
  • Infliximab (Remicade / Renflexis / Inflectra) / Adalimumab (Humira)
  • Hidroxicloroquina (Plaquenil) / Cloroquina
  • Rituximab (Rituxan)
  • Otra quimioterapia
  • Otro
  • Ninguna
• 13- En el pasado, ¿ha recibido tratamiento para la sarcoidosis con (marque todo lo que corresponda)?

  • Prednisona / prednisolona / decadron
  • Metotrexato / Azatioprina (Imuran) / Micofenolato (Cellcept) / Leflunomida (Arava)
  • Infliximab (Remicade / Renflexis / Inflectra) / Adalimumab (Humira)
  • Hidroxicloroquina (Plaquenil) / Cloroquina
  • Rituximab (Rituxan)
  • Otra quimioterapia
  • Otro
  • Ninguna

Supplement S-5

Results of UC/AMC questionnaire

	Covid Positive	Covid negative		Percent with feature	Percent COVID positive	Hazards ratio	95% CI	P	Comments
ALL PATIENTS
Sarcoidosis	66	1906	1972		3.35%	9.15	2.249-37.253	0.002
Cancer	2	545	547		0.37%
LOCAL
OH/KY/IN	3	538	541		0.55%	1.5166	0.2544-9.041		Cincinnati Clinic patients
Cancer	2	545	547		0.37%				Sarc versus cancer
Sarc patients
Male	19	495	514	26.18%	3.70%	1.14	0.675-1.923	>0.10
Female	47	1402	1449	73.82%	3.24%				9 no sex indicated
Black	11	371	382	20.07%	2.88%	0.796	0.4209-1.5066	>0.10
White	55	1466	1521	79.93%	3.62%				9 patients biracial
Roommate with COVID
yes	21	17	38	1.94%	55.26%	23.6772	15.769-35.5514	<0.0001
no	45	1883	1928	98.22%	2.33%
Health care provider
Yes	12	197	209	10.65%	5.74%	1.8565	1.0099-3.4127	0.0464
no	54	1692	1746	88.95%	3.09%
Current meds
Prednisone	24	755	779	39.50%	3.08%	0.8751	0.5343-1.4332	>0.10
No prednisone	42	1151	1193	60.50%	3.52%
Prednisone >10 mg or more	13	361	374	18.97%	3.48%	1.048	0.5774-1.9022	>0.10
Prednisone < 10 mg	53	1545	1598	81.03%	3.32%
Plaquenil	7	239	246	12.47%	2.85%	0.8324	0.3846-1.8016	>0.10
No plaquenil	59	1667	1726	87.53%	3.42%
anti-TNF	6	183	189	9.58%	3.17%	0.9434	0.4131-2.1542	>0.10
no anti-TNF	60	1723	1783	90.42%	3.37%
Cytotoxic	21	537	558	28.30%	3.76%	1.1826	0.7111-1.9666	>0.10
No cytotoxic	45	1369	1414	71.70%	3.18%
Rituximab	6	42	48	2.43%	12.50%	4.0083	1.8213-8.8217	0.0006
No rituximab	60	1864	1924	97.57%	3.12%
Underlying
COPD	12	321	333	16.89%	3.60%	1.0938	0.5917-2.0217	>0.10
	54	1585	1639	83.11%	3.29%
Diabetes	5	292	297	15.06%	1.68%	0.4623	0.1873-1.1408	0.0941
	61	1614	1675	84.94%	3.64%
Heart disease	8	254	262	13.29%	3.05%	0.9002	0.4348-1.8637	>0.10
	58	1652	1710	86.71%	3.39%
Hypertension	15	480	495	25.10%	3.03%	0.8776	0.498-1.5466	>0.10
	51	1426	1477	74.90%	3.45%
Organ involved
Lung	58	1596	1654	83.87%	3.51%	1.3939	0.6721-2.8907	>0.10
	8	310	318	16.13%	2.52%
Cardiac sarc	12	278	290	14.71%	4.14%	1.3303	0.7206-2.4557	>0.10
	54	1628	1682	85.29%	3.21%
Neuro sarc	11	184	195	9.89%	5.64%	1.8228	0.9704-3.4229	0.0619
	55	1722	1777	90.11%	3.10%
Origin
US	50	1551	1601	81.19%	3.12%	0.7516	0.4269-1.3232	>0.10
non US	15	346	361	18.31%	4.16%				No country entered: 10
OH/KY/IN	3	538	541	27.43%	0.55%
	63	1368	1431	72.57%	4.40%
Sarcoid age
Covid Positive							54.5 ± 11.39 years	0.088
Covid negative							53.0 ± 9.60 years
COVID outcome	Home	Hospital	ICU	Ventilator
Sarc	44	9	3	0
Cancer	1	1	0	0
Sarc ≥ 5 yr	48	1274	1322	67.35%	3.63%	1.3321	0.7629-2.359	>0.01
Sarc < 5 yr	16	571	587	29.90%	2.73%
									Hospital considered bad outcome
COVID positive	Home	Hospital							Hazard ration for
Prednisone									Hospitalization
Yes	20	4	24	1.22%	83.33%	0.875	0.2941-2.6036	>0.10
No	34	8	42	2.14%	80.95%
If prednisone
Prednisone ≥ 10 mg	11	2	13	19.70%	15.38%	0.8154	0.2027-3.2794	>0.10
Prednisone < 10mg	43	10	53	80.30%	18.87%
Infliximab
Yes	4	2	6	0.31%	66.67%	0.8154	0.2027-3.2794	>0.10
No	50	10	60	3.06%	83.33%
Plaquenil
Yes	6	1	7	0.36%	85.71%	0.7662	0.1156-5.9785	>0.10
No	48	11	59	3.01%	81.36%
Cytotoxic
Yes	14	7	21	1.07%	66.67%	3	1.0773-83539	0.0355
No	40	5	45	2.29%	88.89%
Rituximab
Yes	6	0	6	0.31%	100.00%	0.3486	0.02303-5.2723	>0.10
No	48	12	60	3.06%	80.00%

* 9 patients did not indicate sex.

† 9 patients biracial

¶ Included inflixiamb, adlimumab, and biosimilars

§ Included methotrexate, azathioprine, mycophenolate, and leflunomide

** 63 patients did not provide information regarding duration of disease.

UC: University of Cincinnati clinic

Supplement S-6

Results from FSR questionnaire

	Covid Positive	Covid negative		Percent with feature	Percent COVID positive	Hazards ratio	95% CI	P	Comments
ALL PATIENTS
Sarcoidosis	13	1603	1616		0.80%
Sarc patients
Male	2	275	277	14.11%	0.72%	0.4545	0.1003-2.0624	>0.10
Female	10	620	630	32.09%	1.59%				709 no sex indicated
Black	3	90	93	4.89%	3.23%	2.817	0.7764-10.2227	>0.10
White	9	777	786	41.30%	1.15%				826 patients biracial
Roommate with COVID
yes	2	3	5	0.25%	40.00%	58.5818	17.2179-1999.317	<0.0001
no	11	1600	1611	82.07%	0.68%
Health care provider
Yes	1	82	83	4.23%	1.20%	1.5392	0.2025-11.6963	>0.10
no	12	1521	1533	78.09%	0.78%
Current meds *									If no response, assume
Prednisone	5	318	323	16.38%	1.55%	2.5019	0.824-7.5971	>0.10	drug not used
No prednisone	8	1285	1293	65.57%	0.62%
Plaquenil	0	115	115	5.83%	0.00%	0.4572	0.02735-7.6429	>0.10
No plaquenil	13	1418	1431	72.57%	0.91%
anti-TNF	1	115	116	5.88%	0.86%	1.0273	0.1348-7.8316	>0.10
no anti- TNF	12	1418	1430	72.52%	0.84%
Cytotoxic	2	272	274	13.89%	0.73%	0.8905	0.1985-3.9952	>0.10
No cytotoxic	11	1331	1342	68.05%	0.82%
Rituximab	1	10	11	0.56%	9.09%	12.1515	1.7255-85.5785	0.0122
No rituximab	12	1592	1604	81.34%	0.75%
Underlying
COPD	3	177	180	9.13%	1.67%	2.3933	0.6648-8.6150	>0.10
	10	1426	1436	72.82%	0.70%
			1616
Diabetes	1	134	135	6.85%	0.74%	0.9142	0.1198-6.9776	>0.10
	12	1469	1481	75.10%	0.81%
			1616
Heart disease	1	116	117	5.93%	0.85%	1.067	0.14-8.1402	>0.10
	12	1487	1499	76.01%	0.80%
			1616
Hypertension	4	275	279	14.15%	1.43%	2.1298	0.6605-6.8673	>0.10
	9	1328	1337	67.80%	0.67%
			1616
Organ involved*									If no response, assume
Lung	10	728	738	37.42%	1.36%	3.9657	1.0954-14.3563	0.0358	not involved
	3	875	878	44.52%	0.34%
			1616
Cardiac sarc	1	12	13	0.66%	7.69%	9.4551	1.3244-67.5027	0.0251
	12	1463	1475	74.80%	0.81%
			1488
Neuro sarc	4	84	88	4.46%	4.55%	7.7172	2.424-24.5693	0.0005
	9	1519	1528	77.48%	0.59%
			1616
Origin
US	NA	NA	0	0.00%	#VALUE!				NOT AVAILABLE
non US	NA	NA	0	0.00%	#VALUE!
			0
Sarcoid age
Covid Positive							54.4 ± 11.29 years	>0.10
Covid negative							56.6 ± 10.39 years
Sarc ≥ 5 yr	8	720	728	38.14%	1.10%	0.5357	0.163-1.7602	>0.01	Information missing on 986 patients
Sarc < 5 yr	4	191	195	10.21%	2.05%
COVID outcome	Home	Hospital	ICU	Vent
Sarc	8	3	0	0					2 no information
			#REF!
COVID positive	Home	Hospital							If in hospital, considered
Prednisone									bad outcome
Yes	3	1	4	6.06%	75.00%	1.05	0.5037-2.1889	>0.10	Hazard ration for
No	5	2	7	10.61%	71.43%				Hospitalization
Infliximab
Yes	0	0	0	0.00%	0.00%	0.7059	0.09617-5.1812	>0.10
No	8	3	11	16.67%	72.73%
Plaquenil
Yes	0	0	0	0.00%	0.00%	0.7059	0.09617-5.1812	>0.10
No	8	3	11	16.67%	72.73%
Cytotoxic
Yes	1	0	1	1.52%	100.00%	1.4286	0.9512-2.1435	0.0849
No	7	3	10	15.15%	70.00%
Rituximab
Yes	0	1	1	1.52%	0.00%	0.3235	0.02872-3.6449	>0.10
No	8	2	10	15.15%	80.00%

Supplement S-7

Results from Netherlands questionnaire

Site: Netherlands
	Covid Positive	Covid negative		Percent with feature	Percent COVID positive	Hazard s ratio	95% CI	P	Comments
Sarcoidosis (996 who live in the Netherlands , out of 1034 respondents )	23	973	996		2.31%
Male	6	418	424	21.60%	1.42%	0.4745	0.1187-1.1932	>0.10
Female	17	553	570	29.04%	2.98%				2 no sex indicated
White	22	932	954	48.60%	2.31%	0.9682	0.1337-7.0165	>0.10
Other	1	41	42	2.14%	2.38%
BMI categories
BMI < 25	8	348	356	18.14%	2.25%	0.958	0.4029-2.2323	>0.10
BMI ≥ 25	15	623	638	32.50%	2.35%
Current meds
Prednisone	4	194	198	10.09%	2.02%	0.84585	0.2919-2.4661	>0.01	of 28 patients the dose is missing
No prednisone	19	779	987	40.65%	2.38%
Prednisone ≥ 10 mg	2	76	78	3.97%	2.56%	1.1795	0.1701-8.1803	>0.10
Prednisone < 10mg	2	90	92	4.69%	2.17%
Plaquenil	1	57	58	2.95%	1.72%	0.7351	0.1008-5.3585	>0.10
No plaquenil	22	916	938	47.78%	2.35%
anti-TNF (infliximab (6), adalimumab (7))	0	76	76	3.87%	0.00%	0.2545	0.01561-4.14497	>0.10
no anti-TNF (de lege cellen uit dezelfde kolommen)	23	897	920	46.87%	2.50%				1 patient was treated with both infliximab and adalimumab
Cytotoxic (methotrexa te (2), azathioprine (3), leflunomide (5))	2	227	229	11.67%	0.87%	0.319	0.07536-1.3502	>0.10
No cytotoxic (lege cellen in dezelfde kolommen)	21	746	767	39.07%	2.74%				3 patients were treated with both methotrexat e and azathioprine
Rituximab
yes	0	1	1	0.05%	0.00%	10.5957	0.9295-120.7801	0.0573
no	23	972	995	50.69%	2.31%
Current medication
yes	7	515	572	26.74%	1.34%	0.40	0.165-0.958	<0.05
no	16	458	474	24.04%	3.38%
Underlying
COPD	0	20	20	1.02%	0.00%	0.9899	0.6217-15.7596	>0.10
	23	953	976	49.72%	2.36%
Asthma	2	80	82	4.18%	2.44%	1.0616	0.2534-4.448	>0.10
	21	893	914	46.56%	2.30%
Diabetes	2	47	49	2.50%	4.08%	1.8406	0.441-7.628	>0.10	(past) use of prednison can be studied additionally
	21	926	947	48.24%	2.22%
Heart failure	0	27	27	1.38%	0.00%	0.7371	0.04592-11.8322	>0.10
	23	946	969	49.36%	2.37%
Circulation	2	35	37	1.88%	5.41%	2.4685	0.601-10.1387	>0.10
	21	938	959	48.85%	2.19%
Hypertension	1	107	108	5.50%	0.93%	0.3737	0.05088-2.7452	>0.10
	22	866	888	45.24%	2.48%
Cancer	0	20	20	1.02%	0.00%	0.9899	0.06217-15.7596	>0.10
	23	953	976	49.72%	2.36%
Organ involved
Lung	20	820	840	42.79%	2.38%	1.2381	0.3724-4.1165	>0.10
no Lung	3	153	156	7.95%	1.92%
heart	0	115	115	5.86%	0.00%	0.1618	0.009892-2.645	>0.10
no heart	23	858	881	44.88%	2.61%
CNS	1	118	119	6.06%	0.84%	0.335	0.04557-2.426	>0.10
no CNS	22	855	877	44.68%	2.51%
Sarcoid age
COVID positive							55.3 ± 6.0 years
COVID negative							55.0±10. 8 years
COVID uncertain							50.5 ± 11.0 years
COVID outcome	Home	Hospital	ICU	Vent
Sarc	20	3	0	0.00%
Sarc ≥ 5 yr	15	678	693	70.14%	2.16%	0.912	0.3758-2.2141	>0.10
Sarc < 5 yr	7	288	295	29.86%	2.37%				8 unknown
			988
Roommates with COVID-19
yes	11	30	41	4.12%	26.83%	21.3516	10.0247-45-4768	<0.0001
no	12	943	955	95.88%	1.26%
			996
Work in healthcare
Yes	4	99	103	10.34%	3.88%	1.8252	0.6331-5.2618	>0.10
No	19	874	893	89.66%	2.13%
			996
COVID positive	Home	Hospital		Perce nt on drug	Percent treate d in hospit al				If in hospital, considered
									bad outcome
									Hazard ration for
Prednisone									Hospitalization
Yes	4	0	4	17.39%	0.00%	0.5714	0.03487-9.3644	>0.10
No	16	3	19	82.61%	15.79%
Prednisone ≥ 10 mg	2	0	2	50.00%	0.00%				TOO SMALL
Prednisone < 10mg	2	0	2	50.00%	0.00%
Infliximab									there were no COVID - 19 positive patients who were treated with infliximab
Plaquenil
Yes	1	0	1	4.35%	0.00%	1.6428	0.1236-21.835	>0.10
No	19	3	22	95.65%	13.64%
Cytotoxic
yes	2	0	2	8.70%	0.00%	1.0476	0.06994-15.6914	>0.10
no	18	3	21	91.30%	14.29%
Rituximab
									none of the COVID-19 positive patients was treated with rituximab

Supplement S-8

Results from Italian Questionnaire

	Covid Positive	Covid negative		Percent with feature *	Percent COVID positive	Hazards ratio	95% CI	P	Comments
ALL PATIENTS
Sarcoidosis	9	502	511		1.76%
Sarc patients
Male	3	205	208	40.70%	1.44%	0.87	0.203-3.628	>0.10
Female	5	293	298	58.32%	1.68%				5 no sex identified
Black	0	6	6	1.17%	0.00%				less than 10 blacks
White	9	483	492	96.28%	1.83%				13 no race indicated
Roommate with COVID
yes	5	3	8	1.57%	62.50%	205.8	36.24-1169.14	<0.0001
no	4	494	498	97.46%	0.80%				5 no answer
Health care provider
Yes	2	45	47	9.20%	4.26%	2.89	0.583-14.324	>0.10
no	7	455	462	90.41%	1.52%				2 no answer
Current meds *
Prednisone	1	260	261	51.08%	0.38%	0.12	0.015-1.017	0.052
No prednisone	7	226	233	45.60%	3.00%				17 no answer
Prednisone>10 mg	1	83	84	16.44%	1.19%
Prednisone<10 mg	0	177	177	34.64%	0.00%	6.38	0.257-158.215	>0.10	only 1 COVID on predniso ne
anti-TNF	0	9	9	1.76%	0.00%	3.23	0.1697-61.655	>0.10
no anti-TNF	6	399	405	79.26%	1.48%				97 no answer
Cytotoxic	2	86	88	17.22%	2.27%	1.55	0.307-7.793	>0.10
No cytotoxic	6	399	405	79.26%	1.48%				18 no answer
Rituximab
No rituximab									No answers on ritux
Underlying
COPD	2	48	50	9.78%	4.00%	2.68	0.542-13.289	>0.10
	7	451	458	89.63%	1.53%				3 no answer
Diabetes	0	32	32	6.26%	0.00%	0.76	0.043-13.328	>0.10
	9	468	477	93.35%	1.89%				2 no answer
Heart disease									not answered
Hypertension	4	126	130	25.44%	3.08%	2.37	0.628-8.980	>0.10
	5	374	379	74.17%	1.32%				2 did not nswer
Organ involved*									If no response , assume
Lung	9	459	468	91.59%	1.92%	1.67	0.096-29.299	>0.10	not involved
	0	40	40	7.83%	0.00%				3 did not answer
Cardiac sarc	2	33	35	6.85%	5.71%	4.03	0.806-20.198	0.0896
	7	466	473	92.56%	1.48%				3 did nto answer
Neuro sarc	0	23	23	4.50%	0.00%	1.07	0.060-18.895	>0.10
	9	476	485	94.91%	1.86%				3 did not answer
Sarcoid age
Covid Positive							55.0 ± 8.63 years	>0.10
Covid negative							51.8 ± 9.74 years
COVID outcome	Home	Hospital	ICU	Vent
Sarc	7	2	1	0

*Percent positive of 511 patients who participated in study.

Supplement S-9

Results from Spanish questionnaire

	Covid Positive	Covid negative		Percent with feature	Percent COVID positive	Hazards ratio	95% CI	P	Comments
ALL PATIENTS
Sarcoidosis	5	100	105		4.76%
Sarc patients
Male	1	27	28	26.67%	3.57%	0.6875	0.08022-5.8917	>0.05
Female	4	73	77	73.33%	5.19%
Other	0	2	2	1.90%	0.00%	DNC
White	5	97	02	97.14%	4.90%				1 No Answer
Current meds
Prednisone	2	40	42	40.00%	4.76%	1	0.1745-5.7322	>0.05
No prednisone	3	60	63	60.00%	4.76%
Prednisone ≥ 10 mg	0	19	19	18.10%	0.00%	0.24	0.01222-4.715	>0.05
Prednisone < 10mg	2	21	23	21.90%	8.70%
Plaquenil	0	6	6	5.71%	0.00%	1.2987	0.07692-21.834	>0.05
No plaquenil	5	94	99	94.29%	5.05%
anti-TNF	1	6	7	6.67%	14.29%	3.5	0.4493-27.264	>0.05
no anti-TNF	4	94	98	93.33%	4.08%
Cytotoxic	0	19	19	18.10%	0.00%	0.3955	0.02278-6.8641	>0.05
No cytotoxic	5	81	86	81.90%	5.81%
Rituximab	0	0	0	0.00%	0.00%	DNC
No rituximab	5	100	105	100.00%	4.76%
Underlying
COPD	0	12	12	11.43%	0.00%	0.6573	0.03854-11.2108	>0.05
	5	88	93	88.57%	5.38%
Diabetes	1	19	20	19.05%	5.00%	1.0625	0.1254-8.9993	>0.05
	4	81	85	80.95%	4.71%
			105
Heart disease	0	5	5	4.76%	0.00%	1.5303	0.09537-24.5561	>0.05
	5	95	100	95.24%	5.00%
			105
Hypertension	0	15	15	14.29%	0.00%	0.517	0.3003-8.9023	>0.05
	5	85	90	85.71%	5.56%
			105
Organ involved									2 no answer
Lung	4	93	97	92.38%	4.12%	0.2474	0.3249-1.8845	>0.05
	1	5	6	5.71%	16.67%
			103
Cardiac sarc	0	4	4	3.81%	0.00%	1.8182	0.116-28.5055	>0.05
	5	94	99	94.29%	5.05%
			103
Neuro sarc	2	6	8	7.62%	25.00%	7.9167	1.5399-40.701	0.0133
	3	92	95	90.48%	3.16%
			103
Origin
SPAIN	4	100	04	5.30%	3.85%
NOT SPANISH	1	0	1	0.05%	100.00%
			105
Sarcoid age
Covid Positive							49.80 ± 9.20years	0.3
Covid negative							44.88 ± 8.82 years
COVID outcome	Home	Hospital	ICU	Vent
Sarc	4	1	0	0
Sarc ≥ 5 yr	4	63	67	3.51%	5.97%	5.0294	0.27827-90.9223	>0.05	1 no answer
Sarc < 5 yr	0	37	37	1.94%	0.00%
			04
COVID positive	Home	Hospital		Percen t on drug	Percent treated in hospital				If in hospital, considered
Prednisone									bad outcome
Yes	2	0	2	3.03%	0.00%				Hazard ration for
No	2	1	3	4.55%	33.33%				Hospitalization
Prednisone ≥ 10 mg	0	0	0	0.00%	#DIV/0!
Prednisone < 10mg	2	0	2	3.03%	0.00%
Infliximab
Yes	1	0	1	1.52%	0.00%
No	3	1	4	6.06%	25.00%
Plaquenil
Yes	0	0	0	0.00%	#DIV/0!
No	4	1	5	7.58%	20.00%
Cytotoxic
Yes	0	0	0	0.00%	#DIV/0!
No	4	1	5	7.58%	20.00%
Rituximab
Yes	0	0	0	0.00%	#DIV/0!
No	4	1	5	7.58%	20.00%
	Covid Positive	Covid negative
Roommate	0	2	2	1.90%	0.00%	3.0909	0.2167-44.087	>0.05	2 no answer
No roommate	5	96	101	96.19%	4.95%
Health provider	3	13	16	15.24%	18.75%	8.0625	1.4614-44.4791	0.0166	3 no answer
No healtg provider	2	84	86	81.90%	2.33%

Supplement S-10

Number of patients and percent positive for individual countries and states within United States

Country	State	Total Number	Number positive	Percent Positive
US	Total	1601	50	3.1%
	Alabama	20	4	20.0%
	Alaska	4	0	0.0%
	Arizona	16	0	0.0%
	Arkansas	10	0	0.0%
	California	50	0	0.0%
	Colorado	21	0	0.0%
	Conneticut	13	1	7.7%
	District of Columbia	3	0	0.0%
	Deleware	5	1	20.0%
	Florida	60	1	1.7%
	Georgia	24	0	0.0%
	Hawaii	1	0	0.0%
	Idaho	4	0	0.0%
	Illinois	61	0	0.0%
	Indiana	46	4	8.7%
	Iowa	17	0	0.0%
	Kansas	5	0	0.0%
	Kentucky	77	8	10.4%
	Lousiana	12	0	0.0%
	Maine	7	0	0.0%
	Maryland	13	0	0.0%
	Massachusetts	38	0	0.0%
	Michigan	51	1	2.0%
	Minnesota	14	0	0.0%
	Mississippi	8	0	0.0%
	Missouri	19	1	5.3%
	Montana	5	0	0.0%
	Nebraska	2	0	0.0%
	Nevada	7	0	0.0%
	New Hampshire	11	0	0.0%
	New Jersey	30	0	0.0%
	New Mexico	3	0	0.0%
	New York	85	3	3.5%
	North Carolina	38	0	0.0%
	North Dakota	2	0	0.0%
	Ohio	468	22	4.7%
	Oklahoma	14	0	0.0%
	Oregon	12	0	0.0%
	Pennsylvania	52	1	1.9%
	Rhode Island	2	0	0.0%
	South Carolina	21	0	0.0%
	South Dakota	3	0	0.0%
	Tennessee	22	2	9.1%
	Texas	42	0	0.0%
	Utah	12	0	0.0%
	Virginia	38	0	0.0%
	Washington	27	0	0.0%
	West Virginia	16	2	12.5%
	Wisconsin	11	2	18.2%
	Wyoming	2	0	0.0%
Non US	Total	361	15
Argentina		1	0	0.0%
Australia		64	0	0.0%
Austria		1	0	0.0%
Belarus		1	0	0.0%
Belgium		2	0	0.0%
Brazil		2	1	50.0%
Canada		62	3	4.8%
Columbia		2	0	0.0%
Czech		1	0	0.0%
Denmark		12	0	0.0%
Ecuador		1	0	0.0%
Egypt		2	0	0.0%
England		96	2	2.1%
Finland		1	0	0.0%
France		5	0	0.0%
Germany		9	0	0.0%
Hungary		1	0	0.0%
India		2	0	0.0%
Ireland		20	0	0.0%
Italy		1	0	0.0%
Mexico		2	1	50.0%
Morroco		1	0	0.0%
New Zealand		4	0	0.0%
Nigeria		3	0	0.0%
Norway		3	0	0.0%
Palestine		2	0	0.0%
Poland		2	0	0.0%
Portugal		3	0	0.0%
Puerto Rico		1	0	0.0%
Romania		3	0	0.0%
Russia		1	0	0.0%
Scotland		9	1	11.1%
Slovania		1	0	0.0%
South Africa		10	0	0.0%
Spain		5	0	0.0%
Sweden		4	3	75.0%
Switzerland		1	0	0.0%
The Netherlands		2	0	0.0%
Turkey		1	0	0.0%
UAE		1	0	0.0%
Wales		1	0	0.0%
Zimbabwe		1	0	0.0%

Introduction

The COVID-19 pandemic has dramatically changed and challenged the practice of medicine. Both sarcoidosis patients and their health care providers are concerned that sarcoidosis may increase the risk of contracting COVID-19 and may be associated with poor outcomes from COVID-19 infection (1). Sarcoidosis patients may have several risk factors associated with an increased rate and a poor outcome from COVID-19 infection including underlying lung disease and the use of glucocorticoids and other immunosuppressive agents (2;3). However, it is not clear that use of immunosuppressive therapy alone is a risk factor for increased rate of COVID-19 infection (4;5). A worse outcome from COVID-19 infection may be result of the common presence of other co-morbidities including heart disease, diabetes, and hypertension (2;6-8). Because of the potential risk of COVID-19 infection in those receiving immunosuppressive medications, sarcoidosis experts have proposed modifying the treatment of sarcoidosis (9). However, these recommendations were based almost exclusively on expert opinion and extrapolation from other medical conditions because of the absence of sarcoidosis-specific outcome data concerning COVID-19 infection.

Because of the lack of specific information concerning risk of acquiring COVID-19 infection and its outcomes in sarcoidosis patients, we initiated an IRB approved questionnaire survey of sarcoidosis patients between April and July 2020 to investigate the prevalence of COVID-19 infection, clinical outcomes and possible risk factors for contracting COVID-19 in several sarcoidosis cohorts across several countries. The questionnaire was distributed through several platforms and was available in four languages: English, Dutch, Italian, and Spanish. Five versions of the questionnaire that were minimally different (vide infra) were distributed to various cohorts. One version of the questionnaire was distributed to sarcoidosis patients who participated in a previously described registry (10). In order to compare these findings with another high-risk group, we also surveyed a cohort of breast cancer patients during this time period. The results of these five questionnaires were pooled and analyzed to provide data concerning the frequency, severity, potential risk factors and outcomes for COVID-19 infection in sarcoidosis patients.

Methods

A questionnaire regarding COVID-19 infection was developed by three of the authors (RPB, EEL, and MAJ). The questionnaire was approved by the University of Cincinnati Institutional Review Board and is shown in Supplement S-1. IRB approval for the FSR questionnaire was obtained from Advarra (Columbus, MD), where the registry number for the FSR Registry is Pro00008556 and modification number for this sub-study is: MOD00087736.

The questionnaire queried whether patients had been infected with COVID-19. If infected, they were asked to provide details regarding level of care (treated at home, hospital, or intensive care unit). They were also queried concerning risk factors for COVID-19 infection including household contacts and whether they were health care providers. The patients were asked if they had underlying medical conditions associated with increased risk for COVID-19 infection. They were also asked to provide information regarding their age, sex, and self-declared race. They provided their current residence, including their state for those living in the United States. Patients with sarcoidosis were queried about the duration of disease, specific organ involvement, and current and past immunosuppressive therapy. The questionnaire responses were collected in an anonymous manner with no patient identifiers captured. At time of completing the questionnaire, patients were asked to provide consent for use of their questionnaire responses. The distribution was meant to reach as wide an audience as possible. Patients were enrolled without incentives, since the survey was anonymous. Respondents were asked to complete the questionnaire even if they did not have any symptoms related to COVID-19 infection. There was no restriction for patients to complete more than one questionnaire.

A total of five questionnaires were distributed (Supplement S-1 to S-4). Table 1 summarizes the features of the five questionnaires. All were based on the University of Cincinnati/Albany Medical Center (UC/AMC) questionnaire. The same questionnaire was distributed to those patients who were Foundation for Sarcoidosis Research (FSR) registry. The questionnaire was translated into Dutch and distributes by the Dutch Sarcoidosis Society (Sarcoidose.nl) and the ild care foundation. The Italian Association for Sarcoidosis patients (ACSI) prepared the Italian version of the COVID-19 questionnaire. The Spanish association of patients with sarcoidosis (ANES-Asociación Española de) prepared a Spanish version of the COVID-19 questionnaire.

Table 1.

Summary of Questionnaires used in Study

Title of questionnaire	Questionnaire version	Invitation distribution	Sarcoidosis patient group	Control group	Dates of Survey	Method of capture	Comments
UC/AMC	UC/AMC English	Posted on FSR website and all patients see at Cincinnati clinic	World wide including Cincinnati OH USA	Cincinnati OH USA	4/1/2020 to 7/1/2020	REDCap	For those in USA, state also indicated
FSR	UC/AMC English	Invitation to those in FSR registry	World wide	N/A	4/6/2020 to 7/1/2020	SurveyMonkey
Dutch	Dutch version UC/AMC	Members of Sarcoidose.nl, and advertisement at the ILD Center of Excellence, Nieuwegein, the Netherlands	Netherlands	N/A	6/29/2020 to 7/29/2020	SurveyMonkey	Collected also if on no medication for sarcoidosis and patient’s BMI
Italian	Italian version of UC/AMC	e-mail contacts of the Italian Association for Sarcoidosis patients (ACSI)	Italy	N/A	4/1/2020 to 7/1/2020	Google Forms
Spanish	Spanish version of UC/AMC	recruited through membership of the Spanish association of patients with sarcoidosis (ANES-Asociación Española de) using e-mail contact	Spain	N/A	May 2020	Google Forms

UC/AMC: University of Cincinnati/Albany Medical Center; FSR: Foundation for Sarcoidosis Research; N/A: not available; ild care: interstial lung disease care; BMI: body mass index

REDcap: Research electronic data capture https://redcap.research.cchmc.org/

SurveyMonkey: www.surveymonkey.com

Google Forms: https://www.google.com/intl/en-US/forms/about/

Statistics

The hazard ratio (HR) with 95% confidence interval (CI) was calculated for various factors for each questionnaire using a statistical software package (MedCalc Software limited, Ostend, Belgium). For those questions which were identical (except for language), the results were summed. HR were calculated for the individual questionnaires and for summary data when available. A p value of less than 0.05 was considered significant.

Results

Supplement Figures S1-S5 show the numbers of patients who completed the questionnaire for each site, including those who did not give consent for final analysis or were excluded for other reasons. Table 2 summarizes the values for 5200 sarcoidosis patients who were analyzed. A total of 116 (2.23%) reported COVID-19 infection. The overall rate of COVID-19 infection is shown for each site and ranged from 0.8 to 4.76%. As shown in the table, there was no significant difference in the rate of infection based on sex, race, or age. In the Dutch questionnaire an additional question revealed that 96 out of 973 COVID-19 negative patients (10%) reported COVID-19 symptoms but were not tested.

Table 2.

Rate of COVID-19 infection for five questionnaires and total

	UC/AMC	FSR	Dutch	Italy	Spain	Total
Total number Sarcoidosis patients	1972	1616	996	511	105	5200
Number COVID positive	66	13	23	9	5	116
Rate of COVID	3.35%	0.80%	2.31%	1.76%	4.76%	2.23%
Percent COVID-19 based on gender
Male	3.70%	0.72%	1.42%	1.44%	3.57%	2.18%
Female	3.24%	1.59%	2.98%	1.68%	5.19%	2.81%
Percent COVID-19 based on race
Black	2.88%	3.23%	NA	NA	NA	2.95%
White	3.62%	1.15%	2.31%	1.83%	4.90%	2.66%
Mean age of patients with or without COVID-19 infection
Age COVID-19 positive, years	54.5 + 11.39*	54.4 + 11.29	55.3 ± 6.0	55.8+ 8.63	49.80 + 9.20	53.5 + 9.47
Age, COVID-19 Negative, years	53.0 + 9.60	56.6 + 10.39	55.0±10.8	51.8 + 9.74	44.88 + 8.82	52.4 + 9.90
Percent COVID-19 infected versus current prednisone therapy
Yes	3.08%	1.55%	2.02%	0.38%	4.76%	2.68%
No	3.52%	0.62%	2.38%	3.00%	4.76%	2.08%
Percent COVID-19 based on living with COVID-19 infected roommate
Roommate COVID positive	55.3%	40.0%	26.8%	62.5%	0.0%	52.7%
No roommate with COVID	2.33%	0.68%	1.26%	0.80%	4.95%	1.53%
Percent COVID-19 based on occupation as health care provider
Health care provider	5.74%	1.20%	3.88%	4.26%	18.75%	5.46%
Not health care provider	3.09%	0.78%	2.13%	1.52%	2.33%	2.82%

NA: not analyzed because less than 10 patients who were this race

*Mean ± standard deviation

The results of the individual questionnaires are provided in Supplement S5-S9. Table 3 summarizes the hazard ratio (HR) for developing COVID-19 for all five sites. Forty-one percent of those with a COVID-19 infected roommate had COVID-19 infection (HR=27.44 (19.798-38.048, 95% confidence intervals, p<0.0001)). We did not collect information about which person was diagnosed first with COVID-19. All but the Spanish questionnaire identified a significant increased risk for COVID-19 for those with a roommate with COVID-19. In the Spanish questionnaire, only two patients reported a COVID-19 infected roommate. Neither of these sarcoidosis patients had COVID-19 infection at the time of completing the survey.

Table 3.

Hazard ratio for developing COVID-19 infection: Summary of all five questionnaires

	Percent with feature	Total pos	Total neg	Total number	Percent Pos	Hazards Ratio	95% CI	P value
Social factors
Roommate COVID positive	1.81%	39	55	94	41.49%	27.44	19.798-38.048	<0.0001
No roommate with COVID		77	5016	5093	1.51%
Health care provider	8.85%	22	436	458	4.80%	2.41	1.532-3.799	0.0001
Not health care provider		94	4626	4720	1.99%
Current treatment for sarcoidosis
Current Prednisone
Yes	30.93%	36	1567	1603	2.25%	1.02	0.689-1.503	>0.10
No		79	3501	3580	2.21%
If taking prednisone:
Prednisone >10 mg or more	22.29%	16	520	536	2.99%	0.98	0.567-1.690	>0.10
Prednisone < 10 mg		57	1812	1869	3.05%
Hydroxychloroquine
Yes	9.20%	8	417	425	1.88%	0.80	0.391-1.628	>0.10
No		99	4095	4184	2.36%
anti-TNF monoclonal antibodies (infliximab, adalmumab)
Yes	7.89%	8	389	397	2.02%	0.89	0.437-1.812	>0.10
No		105	4531	4636	2.26%
Cytotoxic (methotrexate, azathioprine, mycophenolate, leflunomide)
Yes	22.54%	27	1141	1168	2.31%	1.05	0.688-1.615	>0.10
No		88	3926	4014	2.19%
Rituximab
Yes	1.28%	7	53	60	11.67%	5.3993	2.621-11.123	<0.0001
No		100	4528	4628	2.16%
Comorbidities
COPD
Yes	11.43%	16	578	594	2.69%	1.25	0.744-2.108	>0.10
No		99	4503	4602	2.15%
Diabetes mellitus
Yes	10.25%	9	524	533	1.69%	0.74	0.375-1.445	>0.10
No		107	4558	4665	2.29%
Heart disease
Yes	10.40%	9	375	384	2.34%	1.034	0.522-2.048	>0.10
No		75	3234	3309	2.27%
Hypertension
Yes	19.62%	24	1003	1027	2.34%	1.07	0.686-1.666	>0.10
No		92	4115	4207	2.19%
Organ involvement from sarcoidosis
Lung
Yes	73.09%	101	3696	3797	2.66%	2.48	1.446-4.249	0.001
No		15	1383	1398	1.07%
Cardiac
Yes	9.02%	15	442	457	3.28%	1.5	0.878-2.555	>0.10
No		101	4509	4610	2.19%
Neurologic
Yes	8.33%	18	415	433	4.16%	2.02	1.234-3.307	0.0052
No		98	4664	4762	2.06%
Demographic features
Sex
Male	32.42%	31	1420	1451	2.14%	0.7784	0.518-1.117	>0.10
Female		83	2941	3024	2.74%
Race
Black	32.78%	36	1399	1435	2.51%	0.9346	0.633-1.379	>0.10
White		79	2864	2943	2.68%
Duration of disease
Sarcoidosis > 5 years	71.61%	75	2735	2810	2.67%	1.1012	0.713-1.700	>0.10
Sarcoidosis < 5 years		27	1087	1114	2.42%

†Data not available from Dutch registry

CI: confidence interval; anti-TNF: anti-tumor necrosis factor antibody; COPD: chronic obstructive pulmonary disease

The overall risk for health care workers to have COVID-19 infection was 2.41 (1.532-3.799, p=0.0001), with nearly five percent of heath care workers who had sarcoidosis reporting COVID-19 infection. For the Spanish questionnaire, 18.8% of heath care workers reported COVID-19 infection, while less than six percent for all other questionnaires. The HR was only significant for the UC/AMC and Spanish questionnaires.

For sarcoidosis immunosuppressive therapy, rituximab treatment was associated with an increased risk of COVID-19 infection (HR=5.40 (2.621-11.123), p<0.0001). Only the UC/AMC and FSR included more than one patient treated with rituximab. However, both of these identified an increased risk with rituximab use. There was no significant increase in risk for COVID-19 infection for those on any other immunosuppressive therapy. For those receiving prednisone, there was no increased risk for patients prescribed 10 mg or more a day versus a lower dose. A total of 425 patients were prescribed hydroxychloroquine. There was no difference in the risk for COVID-19 among the other questionnaires or for the summary data of all sarcoidosis patients compared to all others. In the Dutch questionnaire, patients who reported to receive any medication for sarcoidosis had a decreased COVID-19 risk (HR=0.40, 0.165 to 0.958, P<0.05). There was no significant difference for the larger UC/AMC questionnaire (HR=1.49, 0.916 to 2.437, p>0.10) or for the combined data.

There was no increased risk with any of the associated with age, race, sex, duration of disease, or the comorbidities investigated. In the Dutch questionnaire, there was no difference in HR for those with a BMI above 25.

There was an increased risk for sarcoidosis patients with lung involvement (HR=2.48 (1.446-4.249), p=0.001). However, the FSR was the only individual questionnaire which identified this as a significant risk. The summary identified neurosarcoidosis as an increased risk factor for COVID-19 infection (HR=2.02 (1.234-3.307), p<0.01). For neurosarcoidosis, there was a significant HR seen for the Spanish and FSR questionnaire and borderline for UC/AMC (p=0.0619).

Most patients responding to the UC/AMC questionnaire provided their country of residence or state of residence if they lived in the United States, and the percentage of patients with COVID-19 infection by residence is shown in Table S-10. There was no significant difference in rates of infections between the United States and non-United States residents. For the United States, there was a wide range but not a significantly different rate of infection between states.

For the UC/AMC questionnaire, we analyzed the risk of COVID-19 infection for two groups of patients seen by either EEL or RPB at the University of Cincinnati from April1 to June 30, 2020. During that time, 547 cancer patients were seen at University of Cincinnati (UC cancer). Two (0.37%) reported COVID-19 infection. Only 3 of 541 (0.55%) sarcoidosis patients seen at the UC sarcoidosis clinic during this time reported COVID-19 infection. The hazard ratio for COVID-19 infection in sarcoidosis patients at the University of Cincinnati was not significantly higher than those with cancer (HR=1.52, 0.254 to 9.041, P>0.10).

Outcome of COVID-19 infection

Table 4 shows the reported rate of hospitalization for those with COVID-19 infection for each questionnaire and for the total group. A mean of 15.8% (range 13 to 27%) of COVID-19 infected patients were hospitalized with about one-third cared for in the intensive care unit at some time during hospitalization.

Table 4.

Outcome of COVID-19 infected patients

	UC/AMC	FSR	Dutch	Italy	Spain	Total
Home	57	8	20	7	4	96
Hospitalized (%)	9 (17.6%)	3 (27.3%)	3 (13.0%)	2 (22.2%)	1 (20%)	18 (15.8%)
Unknown		2

For 105 of the COVID-19 infected patients we had information regarding current immunosuppressive therapy. Nineteen (18.1%) of these were hospitalized. Table 5 summarizes these outcomes and calculates the HR for hospitalization for various immunosuppressive therapies. There were no significant HR with any specific therapy. For the 96 COVID-19 infected patients from three questionnaires (UC/AMC, FSR, and Dutch), we were able to analyze the clinical outcome versus presence of diabetes, hypertension, COPD, and heart disease. Table 6 shows the results of this analysis. Only those with underlying heart disease had an increased rate of hospitalization (HR=3.19, 1.297-7.855, p<0.02).

Table 5.

Outcome of sarcoidosis patients infected with COVID-19 versus immunosuppressive therapy*

DRUG	Home	Hospital	Percent in hospital	HR	95% CI	p
All patients	86	19	18.1%
Prednisone
Yes	29	5	14.7%	0.75	0.293-1.901	>0.10
No	57	14	19.7%
If prednisone
Prednisone > 10 mg	13	2	13.3%	0.76	0.186-3.106	>0.10
Prednisone < 10mg	47	10	17.5%
anti-TNF monoclonal antibodies (infliximab, adalmumab)
Yes	5	2	28.6%	1.65	0.473-5.740	>0.10
No	81	17	17.3%
Hydroxychloroquine
Yes	7	1	12.5%	0.67	0.103-4.416	>0.10
No	79	18	18.6%
Cytotoxic (methotrexate, azathioprine, mycophenolate, leflunomide)
Yes	17	7	29.2%	1.97	0.873-4.440	>0.10
No	69	12	14.8%
Rituximab
Yes	6	1	14.3%	0.78	0.121-5.006	>0.10
No	80	18	18.4%

*Data not available on all patients.

HR: hazard ratio; anti-TNF: anti-tumor necrosis factor antibody;

Table 6.

Outcome of COVID-19 infection versus underlying comorbidities*

	Home	Hospital	Number pos	Rate	HR	95% CI	P
Total
DM	9	2	11	11.46%	1.19	0.308-4.585	>0.10
no DM	72	13	85
HTN	14	5	19	19.79%	2.03	0.784-5.234	>0.10
no HTN	67	10	77
COPD	12	3	15	15.63%	1.35	0.432-4.217	>0.10
no COPD	69	12	81
Heart disease	8	5	13	13.54%	3.19	1.297-7.855	0.0115
no heart disease	73	10	83
Any feature	35	7	42	43.75%	1.12	0.444-2.854	>0.10
No feature	46	8	54

DM: diabetes mellitus; HTN: hypertension; COPD: chronic obstructive pulmonary disease; HR hazard ratio.

*Summary data from UC/AMC, FSR, and Dutch

Discussion

In this analysis of five surveys of sarcoidosis patients from the USA and Europe concerning COVID-19 infection, we found evidence that the rate of COVID-19 infection in sarcoidosis patients was higher than in the general population. We found that sarcoidosis patients who were healthcare workers or were living with a person infected with COVID were at higher risk of COVID infection; these data have been reported in the general population (12;13) and support the well-established fact that COVID-19 is highly infectious and is easily transmitted to individuals who are in close proximity to an actively infected person (14). In regard to immunosuppressive therapy, only rituximab was associated with increased risk for COVID-19 infection in sarcoidosis patients. The lack of association of prednisone use with the development of COVID-19 infection held even when comparing ≥ 10 versus < 10 mg/day. In sarcoidosis patients with diabetes, hypertension, heart disease, and co-existing chronic obstructive pulmonary disease no increased risk of acquiring COVID-19 infection was identified, even though these comorbidities have also been identified as risk factors for COVID-19 infection (6;8;15).

The current data surveyed sarcoidosis patients mostly in United States and Europe from April through July 2020. This time frame co-indices with the onset of the pandemic in these two parts of the world. In our analysis of a questionnaire administered to 5200 sarcoidosis patients, 2.23% or 22,308 cases per million had become infected with COVID-19 during this time. During the time period in which this questionnaire was administered, the number of confirmed cases of COVID-19 in the United States was estimated as 1,060 per million (https://en.wikipedia.org/wiki/Template:COVID-19_pandemic_data/United_States_medical_cases). The same site reported that the cumulative rate of COVID-19 infection in Spain was 5197 per 1 million, Italy 3853 per 1 million, and Netherlands 3141 per 1 million. However, the rate of infection for COVID-19 infection in the general population may be higher. For example, a recent survey using serologic testing found that 2.5% of the Italian population had acquired COVID-19 infection by July 15, 2020 ( http://www.salute.gov.it/imgs/C_17_notizie_4998_0_file.pdf). While there was some variation in the rates of COVID-19 infection from the various questionnaires, overall there was no significant difference in the rate of COVID-19 infection. This was also true when examining the UC/AMC questionnaire, which included 1601 (3.1% infected) responders from US versus 361 (4.2% infected) from outside the United States.

These data suggest that the rate of COVID infection is higher in sarcoidosis patients than the general population. However, the rate of COVID-19 infection varies by the time period as well as from country to country and even within the United States. It is therefore possible, that the rate of COVID-19 in sarcoidosis patients was no different from the general population. A significant number of the sarcoidosis patients completing the UC/AMC questionnaire were seen at the University of Cincinnati Sarcoidosis Clinic, which is in southwestern Ohio. As of July 1, 2020, the reported cumulative rate of COVID-19 infection for this area was 5103 per 1 million (https://coronavirus.ohio.gov/wps/portal/gov/covid-19/dashboards/overview). This is similar to the rate of 5545 per 1 million for our sarcoidosis patients and 3656 per 1 million for the cancer patients. The lower rate of COVID-19 infections for sarcoidosis patient at University of Cincinnati clinic versus other patients completing the questionnaires may be due to lower overall rate of COVID-19 infection in the area and/or the more rigorous criteria for diagnosis, since at our clinic we required verification by culture. This criterion may underestimate the number of cases of COVID-19 infection (16). The hospitalization rates for COVID-19 may be more accurate, since such cases are usually confirmed by cultures.

For sarcoidosis patients, we identified five features associated with increased for COVID-19 infection. Sarcoidosis patients with a COVID-19 infected roommate had a greater than 20-fold increased risk for COVID-19 infection. In one meta-analysis, the risk of in home transmission of disease has been estimated as ten-fold (17). There was also a nearly two-fold increased risk for sarcoidosis patients who were health care workers. This increased risk has been noted for some time (12). The higher risk in Spain may be a reflection that some areas were hit sooner than other parts of the world. The widespread use of N-95 and other respiratory policies later in the pandemic and in other parts of the world may have blunted this risk factor (13;18). Comorbidities in sarcoidosis include diabetes, hypertension, heart disease, and co-existing chronic obstructive pulmonary disease (10;19). These have also been identified as risk factors for COVID-19 infection and more severe disease (2;6;8;15). However, in the current study, none of these was associated with an increased risk for infection.

In regards to immunosuppression therapy, only rituximab was associated with increased risk for COVID-19 infection for sarcoidosis patients. This is not surprising, since rituximab has been noted to have increased the risk for acquiring viral infections (20). In addition, viral infections are more severe when patients are receiving rituximab. We studied only seven patients with COVID-19 infection treated with rituximab.

Sarcoidosis is a multi-organ disease and the effect of sarcoidosis on different organs may affect the patient’s ability to avoid COVID-19 infection. In this study, we found that patients with lung or neurologic involvement were at increased risk for COVID-19 infection. Chronic lung disease has been identified as a risk factor for infection and more severe disease (21).

In terms of the outcomes of COVID-19 infected sarcoidosis patients, we found that less than twenty percent required hospitalization. In a recent, retrospective study of 37 sarcoidosis patients with COVID-19 infection, the rate of hospitalization for infection was 60% and no different from the non-sarcoidosis patients seen at that center (3). However, the rate of adverse outcome as defined by requiring intubation and/or mortality was significantly higher than the non-sarcoidosis patients (3). The current study would have missed the very severe cases, at least the ones who died, as it was a study analyzing a self-reported questionnaire. In our study, the use of immunosuppressive therapy was not associated with a significant increased risk for hospitalization. The overall outcome of these patients appears more favorable than that reported in rheumatoid arthritis patients treated with immunosuppression (22-24). In one study (23), the use of ≥ 10 mg per day of prednisone or its equivalent was associated with increased risk. That study analyzed 600 COVID-19 infected patients and our study may have been underpowered to detect that difference. Interestingly, that study found that anti-TNF therapy was associated with a significantly lower risk for COVID-19 infection (23).

Hydroxychloroquine has been proposed as a potential therapy for patients with COVID-19 infection and ongoing studies are evaluating this drug (25). Over 400 of our sarcoidosis patients were receiving hydroxychloroquine at time of survey. There was no change in the rate of infection or rate of hospitalization for the seven patients who developed COVID-19 infection while on hydroxychloroquine. This has also been noted in a study of patients treated with hydroxychloroquine for various rheumatologic conditions (23).

Several comorbidities have been associated with a worse clinical outcome from COVID-19 infection (7;8;21;23). We were able to analyze the outcome of 96 sarcoidosis patients with COVID-19 infection and reported comorbidities. Underlying heart disease was associated with an increased risk for hospitalization. Other comorbidities examined included diabetes, COPD, and hypertension were not felt to be significant risk factors.

There are several limitations to our study. The questionnaire did not try to quantitate severity of disease, especially significant pulmonary fibrosis. Therefore, we could not comment on impact of severe lung disease on risk or outcome of COVID-19 infection. Because of the low number of incident cases, we may have been underpowered to detect smaller, but significant risk factors including comorbidities and the impact of immunosuppression therapy. The questionnaires were completed by the patients, usually on-line. With the exception of those seen at the University of Cincinnati, there was no attempt to verify COVID-19 infection. Patients who had severe disease or even died would be unlikely to be able to complete the questionnaire, so this group was underrepresented. Also, the rate of COVID-19 infection in sarcoidosis patients varies based on local conditions and time into the pandemic. The rate of COVID-19 infection in the general population during the study period may be better understood over time, especially as serologic testing becomes more widely used. However, the rate of infection for COVID-19 infection in the general population may be higher. We compared our results to a standard reporting site which provided cumulative rates for various parts of the world. In the sub-study at University of Cincinnati, the rate of infection was not significantly different from cancer patients seen at the same time period. Future reports may provide a better understanding of the rate of COVID-19 infection in the community studied. Future rates may be affected as vaccines become available. Vaccines for other conditions have proved to be effective in preventing infections in sarcoidosis patients (26).

In summary, our data suggests an increased rate of COVID-19 infection in sarcoidosis patients. However, when compared to non-sarcoidosis patients in the same area and time of the study, the rate of COVID-19 infection was not significantly different. The most obvious risk factor for COVID-19 infection was having a roommate with COVID-19. This means that hygiene measures and distancing are extremely important at home as well as in public. To facilitate research on prevalence and risk factors of COVID-19 infection in chronic diseases, sarcoidosis specifically, it would be helpful to report in population registries not only numbers of patients with COVID-19, but also their characteristics, such as comorbidities and medication use.