The COVID-19 pandemic is a very dynamic event. Recommendations and instructions from the Robert Koch Institute and the authorities may change at short notice and may go beyond or replace the recommendations made here.

The recommendations summarized here are written and regularly updated by API immunologists from major immunodeficiency centers (Berlin, Munich, Freiburg, Ulm, Vienna, Zurich*). As no reliable data on the topic from clinical studies is available to date, this is an expert opinion based on currently available information.

http://www.kinderimmunologie.de/neuartiges-Coronavirus

Information on SARS-CoV2 and COVID-19

Status of the information: 02.11.2020

The SARS-CoV-2 pandemic is a very dynamic event. Recommendations and instructions from the Robert Koch Institute (RKI) and other health authorities may change at short notice and therefore temporarily deviate from the recommendations given here. The recommendations summarized here are written and regularly updated by API immunologists from major immunodeficiency centers (Berlin, Munich, Freiburg, Ulm, Vienna, Zurich)*.

How does the API assess the situation for patients with congenital immunodeficiencies?

For fundamental reasons, patients with congenital immunodeficiencies are initially assessed as high-risk patients with regard to the SARS-CoV-2 pandemic. Due to the less responsive immune system, these patients could fall more seriously ill after an infection and remain infectious for longer.

However, the blanket classification of all immunodeficiency patients as high-risk patients does not do justice to the course of infection observed to date. Our assessment as a guide for patients and their treating physicians is based on our efforts to identify risks for school attendance and resumption of attendance work, but also not to restrict patients unnecessarily. The assessment is regularly adapted on the basis of the discussion of current case reports and case series on the course of infection in immunodeficiency patients, which we have at our disposal together with our international contacts. This expert assessment is not legally binding.

We suggest that the treating immunodeficiency specialist classifies patients into two groups:

1. Patients with immunodeficiency who do not have a recognizably increased risk of becoming seriously ill from SARS-CoV-2
2. Patients with immunodeficiency who have at least one risk factor for becoming seriously ill from SARS-CoV-2.

The known general risk factors include

• Severe lung or heart disease
• Diabetes mellitus
• Body mass index (BMI) over 30
• Age over 60 years.

The following specific risk factors are also relevant:

• Severe pulmonary viral infections in the past
• Chronic lung changes
• Patients with a pronounced T-cell defect ("combined immunodeficiency")
• Patients with limited production or efficacy of type I interferons
• Possibly other individual genetically defined immunodeficiencies

The risk of severe SARS-CoV-2 infection is probably higher for the patient group mentioned under 2. It can also be assumed that in some of these patients, even with a mild course, virus excretion is significantly prolonged. More far-reaching measures are therefore recommended for this patient group, and the recommendations for risk groups should be followed as part of any relaxation measures.

For many patients, classification into the two risk groups will not be clearly possible based on the current data, so that in case of doubt, the individual situation (type of immunodeficiency, living situation, place of residence, therapy, etc.) should be discussed with the family physician and, if necessary, the attending physician at your immunodeficiency center.

The recommended special protective measures for at-risk patients are summarized by the RKI HERE.

What experience is now available on COVID-19 courses in patients with immunodeficiency?

In a recently published paper (J Allergy Clin Immunol. 2020 Sep 24;S0091-6749(20)31320-8.), 94 patients (different age groups) with congenital immunodeficiencies who had undergone SARS-CoV-2 infection were reported. 53 patients had an antibody deficiency disease, 14 had a combined immunodeficiency, 16 had a genetic disorder of immune regulation, 6 had a granulocyte defect, 3 had a disorder of innate immunity and 2 had bone marrow failure. Ten patients were asymptomatic, 24 could be treated as outpatients and 59 were hospitalized. Of the hospitalized patients, 29 developed respiratory insufficiency and 15 were admitted to an intensive care unit. Seven adults and two children died, all of whom had relevant general risk factors.

Two other papers reported that patients with genetic disorders of the type I interferon response (IFNalpha and omega) also develop more severe courses of COVID19 (Science. 2020 Oct 23;370(6515):eabd4585. Science. 2020 Oct 23;370(6515):eabd4570. ; J Allergy Clin Immunol Pract 2020 Oct 8;S2213-2198(20)31102-8. doi: 10.1016/j.jaip.2020.09.052. Online ahead of print). It has also been shown that autoantibodies against type I interferons can lead to more severe courses.

Severe COVID-19 courses in patients with agammaglobulinemia (including Bruton's disease) have not yet been described (Pediatr Allergy Immunol 2020, PMID: 32319118; PMID: 32333914). Similarly, no severe courses in patients with selective IgA deficiency and neutropenia/phagocyte function defects (e.g. septic granulomatosis) without additional general risk factors have been published to date.

In summary, the risk for patients with immunodeficiencies must be considered in a very differentiated manner and an increased risk can be determined for individual diseases. However, according to current knowledge, many children and adolescents with immunodeficiencies without additional general risk factors (see above) do not have an increased risk of a severe course of COVID-19 disease. Therefore, if in doubt, contact should be made with the attending physicians.

What provisional recommendations are there for families with children with congenital immunodeficiencies when daycare centers and schools reopen?

Based on the above-mentioned distinction between 2 groups, the general guidelines apply to children from patient group 1 and school/daycare center attendance can take place if there are corresponding regional guidelines.

For children from patient group 2, the guidelines for risk groups apply and exemption from school attendance may be indicated by the attending physician. This may also include the exemption of a necessary caregiver from work.

Older patients in particular should work with their attending physician to individually consider how contact with children or grandchildren who attend school or kindergarten can be organized as safely as possible.

Important general protective measures for Group 2 patients in addition to the generally applicable AHA(L) rules are

• Limiting contact with other people to the nuclear family
• For unavoidable encounters outside the nuclear family, the patient and contact persons should wear an FFP2 protective mask
• Avoid unnecessary exposure situations (e.g. make use of family and neighborly help when shopping, home office where possible and sensible)
• Check the place of work, discuss this with the employer and arrange it accordingly. If no option is available, find alternative options (extended home office, other workplace, leave of absence, etc.)
• In special risk constellations (e.g. SARS-CoV-2 infected persons in your own household), determine how to deal with SARS-CoV-2 infected persons in the household (e.g. sleeping and staying in separate rooms; eating meals separately; spatial separation of siblings)

Should the immunoglobulin dose or concomitant medication be changed?

Intravenous or subcutaneous immunoglobulin administration protects patients with antibody deficiency against many infections, especially respiratory infections, and should be continued in any case. If the immunoglobulin dose was previously insufficient, it should always be adjusted. However, immunoglobulin administration does not protect against infections with the SARS-CoV-2 coronavirus. Increasing the immunoglobulin dose solely for this purpose has no protective effect and is not indicated. Current immunoglobulin preparations do not contain antibodies against SARS-CoV-2.

Should anti-inflammatory or immunosuppressive drugs be avoided?

So far, there is no clear data on whether the therapeutic doses of these drugs used affect the course of COVID-19. The following therefore applies: immunosuppressive medication should not be reduced or even discontinued as a precautionary measure without consulting the physician treating you.

Should visits to the physician be made?

Regular medical monitoring is an essential element of the treatment of patients with congenital immunodeficiencies. This includes visits to the family physician/pediatrician as well as to a specialist. Routine medical check-ups, preventive examinations and vaccinations should be carried out. Find out about the procedures in your practices/outpatient clinics and make appointments whenever possible. Many physicians also offer telephone or video consultations.

What should I do if the virus is detected in an immunodeficiency patient?

People with virus detection in a throat swab are considered potentially infectious and must comply with the quarantine measures recommended by the RKI. When visiting a physician, a mask must be worn to prevent the virus from being exhaled unhindered. FFP2 masks should preferably be worn here (under NO circumstances a mask with an exhalation valve!).

If the virus is detected (even without clinical signs of infection), possible changes to the therapy for the immunodeficiency should be agreed with the physician treating you. If SARS-CoV2 infection requires treatment, the therapy should be discussed with the treating immunodeficiency center at an early stage.

What if I have been infected with SARS-CoV-2?

There are initial indications that some patients with immunodeficiencies shed virus for longer than immunocompetent people. It is therefore conceivable that patients with immunodeficiency may remain infectious beyond the specified (country-specific) quarantine period. This may be the case even if they are clinically well. For this reason, patients with immunodeficiency should have a control swab taken before the end of quarantine and - in consultation with the attending physician - weekly afterwards if necessary, until it is negative twice.

It is currently unclear whether and for how long a past infection protects against re-infection. This applies in particular to patients with immunodeficiencies, so they should continue to take the recommended protective measures even after surviving an infection.

Will there also be a vaccine for immunodeficiency patients?

Many patients with antibody deficiency diseases are unable to produce protective antibodies after vaccination. However, some vaccines will be able to induce T-cell immunity against SARS-CoV-2, which may provide some protection. Due to the wide variety of immunodeficiencies and vaccines under development, as with other vaccine-preventable diseases, targeted vaccination counseling will be required for these patients. For patients who are unable to build up a protective immune response themselves, passive immunizations by administering antibodies from SARS-CoV-2-immune donors or monoclonal antibodies could become an alternative in the future. The environmental vaccination of family members and close household contacts is therefore of great importance. The vaccination strategy, especially for vulnerable population groups, is currently being developed by the Federal Ministry of Health (prioritization by STIKO, Ethics Council, Leopoldina pending; https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/3_Downloads/C/Coronavirus/Impfstoff/Nationale_Impfstrategie.pdf).

What other special sources of information are there for patients with immunodeficiencies?

The International Patient Organization for Immunodeficiencies IPOPI has compiled important information on frequently asked questions HERE.

How can I help to make information on SARS-CoV-2/ COVID-19 more reliable for immunodeficiency patients?

If you are found to be infected with SARS-CoV-2 (with or without symptoms), please inform your treating immunodeficiency specialist about the infection and ask them to report this infection in a European patient registry (COPID19).

https://dsp.institutimagine.org/copid/connexion.php?login=nmahlaoui&script_appel=/copid/index.ph

*Authors:

Prof. Dr. Michael Albert; Prof. Dr. Horst von Bernuth; Prof. Dr. Kaan Boztug; Prof. Dr. Stephan Ehl; Prof. Elisabeth Förster-Waldl, Prof. Dr. Bodo Grimbacher; PD Dr. Dr. Fabian Hauck; Prof. Dr. Philipp Henneke; Prof. Dr. Jana Pachlopnik-Schmid; Prof. Dr. Janine Reichenbach; Prof. Dr. Ansgar Schulz; Dr. Volker Umlauf; Prof. Dr. Klaus Warnatz.

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study. J Allergy Clin Immunol. 2020 Sep 24:S0091-6749(20)31320-8. doi: 10.1016/j.jaci.2020.09.010. epub ahead of print. PMID: 32980424. IUIS Committee of Inborn Errors of Immunity, Warnatz K, Sullivan KE, Tangye SG et al.