Rostrum

Latin American consensus on the supportive

management of patients with severe combined
immunodeficiency
Juan Carlos Bustamante Ogando, MD,a Armando Partida Gayta
n, MD,a Juan Carlos Aldave Becerra, MD,b
Aristo


teles Alvarez Cardona, MD, Liliana Bezrodnik, MD, Arturo Borzutzky, MD,f Lizbeth Blancas Galicia, MD, MSc,a
c d,e

Diana Cabanillas, MD,g Antonio Condino-Neto, MD, PhD,h Agust
ın De Colsa Ranero, MD,i
Sara Espinosa Padilla, MD, PhD,a Juliana Folloni Fernandes, MD,j Jorge Alberto Garc
ıa Campos, MD,k
He
ctor Go
lez Serrano, MD,a Alonso Gutie

mez Tello, MD,l Mar
ıa Edith Gonza
rrez Herna

ndez, MD,m
V
ıctor Manuel Herna
ndez Bautista, MD, Gabriele Ivankovich Escoto, MD, Alejandra King, MD,o
m n,u

Juliana Lessa Mazzucchelli, MD,p Beatriz Adriana Llamas Guille
n, MD,q Saul Oswaldo Lugo Reyes, MD, MS,a
Sarbelio Moreno Espinosa, MD, Mat
ıas Oleastro, MD, Francisco Otero Mendoza, MD,i
r s

Mar
ıa Cecilia Poli Harlowe, MD, PhD,t Oscar Porras, MD, PhD,u Nideshda Ramirez Uribe, MD,v Lorean Regairaz, MD,g
Francisco Rivas Larrauri, MD,m Federico Jose
Saracho Weber, MD,w Anete S. Grumach, MD,x
Tamara Staines Boone, MD,y Beatriz Tavares Costa-Carvalho, MD,z Marco Antonio Yamazaki Nakashimada, MD,m and
Francisco Javier Espinosa Rosales, MDaa Mexico City, Aguascalientes, Monterrey, Puebla, Morelos, and Chihuahua,
Mexico; Lima, Peru; Buenos Aires and La Plata, Argentina; Santiago, Chile; Sao Paulo, Brazil; and San Jos

e, Costa Rica

Severe combined immunodeficiency (SCID) represents the submitted the interventions for expert consensus through a
most lethal form of primary immunodeficiency, with modified Delphi technique. Interventions are grouped in 10
mortality rates of greater than 90% within the first year of topic domains, including 123 ‘‘agreed’’ and 38 ‘‘nonagreed’’
life without treatment. Hematopoietic stem cell statements. This document intends to standardize supportive
transplantation and gene therapy are the only curative clinical care of patients with SCID from diagnosis to
treatments available, and the best-known prognostic factors definitive treatment, reduce disease burden, and ultimately
for success are age at diagnosis, age at hematopoietic stem cell improve prognosis, particularly in countries where newborn
transplantation, and the comorbidities that develop in screening for SCID is not universally available and delayed
between. There are no evidence-based guidelines for diagnosis is the rule. Our work intends to provide a tool not
standardized clinical care for patients with SCID during the only for immunologists but also for primary care physicians
time between diagnosis and definitive treatment, and we aim and other specialists involved in the care of patients with
to generate a consensus management strategy on the SCID. (J Allergy Clin Immunol 2019;nnn:nnn-nnn.)
supportive care of patients with SCID. First, we gathered
available information about SCID diagnostic and therapeutic Key words: Severe combined immunodeficiency, consensus, trans-
guidelines, then we developed a document including plantation, supportive measures, treatment, immunodeficiency,
diagnostic and therapeutic interventions, and finally we primary immunodeficiency

From athe Immunodeficiencies Research Unit, ithe Department of Infectious Diseases, ciencias e innovaci
on en medicina, Universidad del Desarrollo–Clinica Alemana, San-
m
the Department of Clinical Immunology, and vthe Hematopoietic Stem Cell Trans- tiago; uPediatric Immunology and Rheumatology, Hospital Nacional de Ni~nos ‘‘Dr.
plantation Unit, Instituto Nacional de Pediatria, Mexico City; bthe Division of Allergy Carlos S
aenz Herrera,’’ San Jos
e; wHospital Infantil de Especialidades, Chihuahua;
x
and Immunology, Hospital Nacional Edgardo Rebagliati Martins Lima; cUnidad de In- the Division of Clinical Immunology, Facultade de Medicina ABC, Sao Paulo; zthe
vestigaci
on en Inmunolog
ıa Cl
ınica y Alergia, Aguascalientes; dthe Immunology Allergy and Immunology Unit, Department of Pediatrics, Universidade Federal de
Department, Hospital de Ni~nos ‘‘Ricardo Guti
errez,’’ Buenos Aires; eCentro de In- Sao Paulo, Santo Andre, Sao Paulo; and aaFundaci
on Mexicana para Ni~nas y Ni~nos
munolog
ıa Cl
ınica ‘‘Dra. Bezrodnik,’’ Buenos Aires; fthe Department of Pediatric In- con Inmunodeficiencias Primarias (FUMENI), Mexico City.
fectious Diseases and Immunology, School of Medicine, Pontificia Universidad This work was partially funded by Fundaci
on Mexicana para Ni~nas y Ni~nos con
Cat
olica de Chile, Santiago; gthe Immunology Unit, Children’s Hospital ‘‘Superiora Inmunodeficiencias Primarias (FUMENI).
Sor Maria Ludovica,’’ La Plata; hthe Department of Immunology, Institute of Biomed- Disclosure of potential conflict of interest: The authors declare that they have no relevant
ical Sciences, University of Sao Paulo; jDepartamento do Hematolog
ıa e Transplante conflicts of interest.


de Medula Ossea, Hospitalo Israelita Albert Einstein, Sao Paulo; kthe Infectious Dis- Received for publication December 4, 2018; revised July 30, 2019; accepted for publica-
ease Department and ythe Clinical Immunology Department, Hospital de Especiali- tion August 5, 2019.
dades, Monterrey; lthe Immunology Department, Hospital para el Ni~no Poblano, Corresponding author: Juan Carlos Bustamante Ogando, MD, Av. Insurgentes Sur
Puebla; nthe School of Medicine, University of Costa Rica, San Jos
e; othe Division 3700-c, Cuicuilco, Mexico City 04530, Mexico. E-mail: drbustamante_inp@
of Pediatric Immunology, Hospital Luis Calvo Mackenna, Santiago; pthe Department hotmail.com.
of Pediatrics, Universidade Federal de Sao Paulo; qthe Immunology Department, Hos- 0091-6749/$36.00
no Morelense, Morelos; rDepartment of Infectious Diseases, Hospital In-
pital del Ni~ Ó 2019 American Academy of Allergy, Asthma & Immunology
fantil de M
exico ‘‘Federico G
omez,’’ Mexico City; sthe Department of Immunology https://doi.org/10.1016/j.jaci.2019.08.002
and Rheumatology, Hospital de Pediatr
ıa J. P. Garrahan, Buenos Aires; tInstituto de

1
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in different specialized referral centers have given way to

Abbreviations used recommendations for supportive treatment.4,7,8
HSCT: Hematopoietic stem cell transplantation The prognosis and survival of patients with SCID after HSCT
NBS: Newborn screening are better when it is performed at an early age and without
PID: Primary immunodeficiency comorbidities or active infections at the time of the procedure. In
SCID: Severe combined immunodeficiency
an ideal scenario patients with SCID are detected by using
neonatal screening, and HSCT at less than 3.5 months of age is
performed in the absence of serious and/or active infections,
allowing a success rate and survival at 5 years of greater than
Primary immunodeficiencies (PIDs) comprise more than 350
90%.9 However, the most common scenario in Latin America and
hereditary diseases that affect the development, function, or both
most parts of the world where NBS is not yet routinely available is
of the immune system.1 Severe combined immunodeficiencies
the diagnosis of SCID once signs and symptoms have developed,
(SCIDs) constitute a heterogeneous group of genetic defects
which often include infections and serious complications and
that result in failure in the number and/or function of T lympho-
delayed referral to a specialized center for definitive treatment.11
cytes, profoundly affecting cellular and humoral adaptive
It is very likely that a large number of patients die of serious
immunity.2 SCID affects approximately 1:55,000 live newborns
infections without receiving a proper diagnosis of SCID. Timely
and represents the most lethal spectrum of PIDs.3 Without timely
diagnosis and treatment affect not only survival but also the
treatment, SCID results in high mortality rates during the first year
quality of life of patients and their families and the economics
of life.2
of health systems.12-14 The median age at diagnosis in subjects
presenting with typical clinical manifestations is 179 days
CLINICAL PICTURE AND DIAGNOSIS OF SCID (36-4916 days) compared with the median of 14 days
SCID typically manifests in the first 6 months of life with (0-80 days) reported for subjects receiving a diagnosis based on
severe and/or persistent infections caused by any type of a family history of SCID or neonatal screening (P <.001).15 These
microorganism (ie, bacteria, viruses, fungi, and mycobacteria), differences also affect the time to definitive treatment: patients in
poor growth, and chronic diarrhea. Physical examination usually Latin America receive curative treatment at a median of 214 days
shows the absence of lymphoid tissue, and routine laboratory tests of life compared with 67 days of life for patients in the
usually document lymphopenia (<3000 cells/mm3) and United States.15
hypogammaglobulinemia, with absent thymus demonstrated by In Latin America social, environmental, and demographic
means of chest radiography or ultrasonography.4 Peripheral conditions introduce added challenges. First, no country has
blood lymphocyte subsets typically show low numbers of implemented universal neonatal screening, and because of the
T lymphocytes (CD31, CD41, and CD81) with or without a relative rarity of the diagnosis, there is a low index of diagnostic
decrease in the number of B lymphocytes (CD191) and/or natural suspicion by primary care physicians.16
killer cells (CD161CD561). Lymphoproliferation studies with Second, with the exception of Ecuador, all countries in the
different stimuli show defects in the activation and proliferation region apply universal vaccination against tuberculosis at birth
of T lymphocytes.2,4 Confirmation of pathogenic variants in genes with the BCG vaccine,17 causing disseminated BCG in 51% to
known to cause SCID helps for a definitive diagnosis, although 65% of patients with SCID.18
therapeutic interventions should not be delayed while waiting Third, resource limitations, medical infrastructure, few HSCT
for a genetic diagnosis when clinical and immunologic features centers, and scarce donor registries limit access and opportunities
are compatible with SCID.1 Family history of SCID, consanguin- to perform early definitive treatments.11 In this context less than
ity, early deaths, or severe infections at an early age might be 30% of patients receiving a diagnosis of SCID receive curative
important clues to diagnosis.4 treatment, with a success rate ranging from 40% to 65% (personal
Given that SCID is rare and usually asymptomatic at birth, communications). The waiting time between diagnosis and HSCT
population-based newborn screening (NBS) using a T-cell is approximately 4 to 6 months, which adds to the diagnostic
receptor DNA excision circle assay on dried blood spots is delay and reduces the probability of achieving HSCT under
currently a useful strategy to identify patients with SCID earlier optimal conditions (Fig 1).
and before the development of infectious complications.5 In the period between diagnosis and curative treatment,
Universal NBS has been implemented in the United States and infectious, inflammatory, and autoimmune complications affect
some other regions but is still not a reality in most parts of the the prognosis of patients, even if they manage to receive such
world.5,6 treatment. Viral, bacterial, fungal, and often polymicrobial
infections are responsible for the greatest mortality.10,15 The
supportive treatment provided during the waiting period for
TREATMENT AND PROGNOSIS curative treatment is critical to achieve ideal conditions in patients
Curative treatments for SCID depending on the molecular and improve survival, and measures should be implemented from
defect and availability are hematopoietic stem cell transplantation the time SCID diagnosis is considered (Fig 2).19 In our clinical
(HSCT) or gene therapy.2 However, none of these interventions practice we have identified great heterogeneity in the diagnostic
can be provided immediately, resulting in a lapse between and therapeutic interventions received by patients with SCID
diagnosis and the application of such treatments. This lapse among different centers and even among different physicians
represents a critical period during which the implementation of within the same center. We consider this heterogeneity to result
correct medical interventions allows patients to reach a curative in deleterious effects for these patients, and furthermore, it should
treatment under the best possible clinical conditions. In this sense be considered that in most cases, the initial supportive treatment
the observations of several cohorts of patients with SCID treated given to patients with SCID will be initiated by primary care
J ALLERGY CLIN IMMUNOL BUSTAMANTE OGANDO ET AL 3
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FIG 1. Ideal versus common scenarios for patients with SCID. In places where SCID NBS is not routinely
available, delayed diagnosis and treatment have a considerable effect on survival and overall prognosis.
Clinical awareness and initiation of supportive measures from the time of diagnostic suspicion might allow
patients with SCID to receive definitive treatment in better clinical conditions.

FIG 2. Strategies to improve SCID prognosis. SCID treatment requires specialized and multidisciplinary
clinical care. Many strategies can be implemented at different time points and health care levels to improve
prognosis and survival. GvHD, Graft-versus-host disease.

physicians, pediatricians, and physicians in emergency services for such a period between diagnosis and curative treatment and
and not by an immunologist with experience with these diseases. certainly not in the context of developing countries, such as those
For these reasons, the creation of a document that is agreed in the region of Latin America.
upon by experts and allows the establishment of sequential Developing a consensus regarding the diagnostic and
guidelines for patients with a suspected or confirmed diagnosis therapeutic interventions to be implemented in this critical period
of SCID is a useful tool with a potential beneficial effect on will establish a starting point to (1) know our practices, (2) create
patient care, with the ultimate objective of facilitating curative a reference document to homogenize clinical care, (3) compare
treatments under better clinical conditions. To the best of our our care against other references, and (4) allow improvement of
knowledge, there are no published clinical practice guidelines or the clinical care of these patients and, consequently, their
consensus that focus particularly on specific recommendations prognosis and survival.
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FIG 3. Supportive measures for patients with SCID are classified in 10 domains based on the main clinical
objectives.

FIG 4. Consensus document flowchart. The Delphi method has been widely used to establish guidelines in
areas of health care and research. It is particularly useful in situations in which there is a lack of agreement,
incomplete knowledge, uncertainty, or lack of evidence.22 The final document includes 161 interventions, of
which 123 (76.4%) achieved consensus (Table I) and 38 (23.6%) did not reach consensus (see Table E1).
ANOVAmr, Repeated-measures ANOVA.

CONSENSUS ON SCID SUPPORTIVE MEASURES A document concerning the management of patients with SCID
Using a defined methodology and a modified Delphi technique, detected by using neonatal screening in the United States was
our objective is to propose a Latin American consensus for the recently published in which diagnostic and therapeutic
supportive treatment of patients with SCID, from diagnostic interventions are proposed to be performed before definitive
suspicion to the execution of curative treatment, considering the treatment, many of which coincide with the strategies expressed
clinical and sociodemographic particularities of the region. in our consensus.20 During the annual Clinical Immunology
First, we conducted a structured and exhaustive search of the Society meeting in Toronto 2018, an abstract by Heimall et al
literature on diagnostic and therapeutic interventions for the presented a survey of 51 specialists from 43 specialized centers
support and treatment of patients with SCID. We also contacted in the United States belonging to the Primary Immune Deficiency
SCID experts from PID reference centers (see the Acknowledge- Treatment Consortium on the management of patients with SCID
ments section) in Europe, the United States, Canada, and Latin detected by means of neonatal screening during the period from
America and specifically requested written documents that guide diagnosis to HSCT. The survey showed that one third of the
the clinical care of patients with SCID in their institutions. We centers lack established practice guidelines, as well as significant
found a lack of specific written protocols for the management of heterogeneity in intercenter practices, with respect to
patients with SCID in specialized centers in developed countries, antimicrobial prophylaxis and infection monitoring, performance
and even in these centers, most clinical decisions are based on the of diagnostic studies, and general measures to avoid infectious
experiences of the local clinicians (personal communications). complications. Despite neonatal screening, up to 42% of the
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TABLE I. Consensus interventions for supportive management of patients with SCID

Intervention Kappa value

1. Isolation and protection methods to reduce transmission of infectious-contagious diseases

All patients who are hospitalized should be admitted to isolated rooms. 0.94
All hospitalized patients must be kept in conditions of strict protective isolation (single-patient rooms with positive pressure and 0.89
high-efficiency particulate air filters, restriction of visits, and use of gloves, face masks, hats, boots, hand washing with a 3-step
technique with 4% chlorhexidine or iodopovidone or equivalent, and a sterile diet).
If the patient is in good general condition (asymptomatic), he or she can be taken care of at home under the following home conditions: >0.75
d The house where the child is cared for must have drinking water, electricity, drainage, and some means of communication
(telephone or cell phone).
d Patient care is limited to 1 or 2 family members.
d There is no exposure to contact with other children.
d Visits are strictly restricted.
d There is no exposure to animals of any kind.
d Hand washing by caregivers must be done with alcohol, chlorhexidine, or similar.
d Exposure to sick family members must be restricted.
d Reliable parents and/or caregiver must have been previously trained in the diagnosis and care of the patient.
d There must be no vaccination of caregivers with live agents (varicella, rotavirus, yellow fever, oral polio, rubella, mumps,
cholera, or oral typhoid).

At the entrance to the room of a patient with SCID, there must be visible notifications of the preventive and general care measures 1.00
to be carried out by health care and related personnel before entering the room.
All persons (caregivers, students, nurses, medical personnel, and cleaning staff) who enter the patient’s room should: >0.75
d wear face masks and
d use a gown that is exclusive for that room.

Student (eg, medicine, nursing, or nutrition) access must be restricted to the rooms of patients with SCID in teaching hospitals. 0.82
The nurse in charge of the care of patients with SCID should avoid simultaneous contact with other patients with infectious diseases. 1.00
Specific nursing staff should be assigned for the care of patients with SCID, attempting to reduce as much as possible the rotation 0.93
of nursing staff for these patients.
Entry of people to the room should be restricted as much as possible. 1.00
Avoid contact with any person with symptoms of any infectious process, including mild symptoms (eg, cold, cough, or diarrhea). 1.00
Avoid contact with other children to avoid contagious infectious diseases. 0.94
In case the patient requires a study that cannot be performed in his or her room (ie, imaging studies), the patient should be treated 0.94
in the respective area without waiting and without being in contact with other patients.
All medical and nursing staff participating in the care of these patients should receive special training. 1.00
Disinfect toys and electronic devices, such as telephones, tablets, and video games, before they enter the room of a patient with 1.00
SCID.
Medical equipment (eg, stethoscope, sphygmomanometer, or monitor) should be exclusively assigned for use in a patient with 1.00
SCID.
2. Antimicrobial prophylaxis
Prophylaxis against bacteria and Pneumocystis jirovecii should be administered with TMP/SMX. 1.00
Prophylaxis with TMP/SMX can begin after 2 weeks of life, as long as the concentration of bilirubin is normal. 0.78
Prophylaxis against fungal infections should be administered with itraconazole (10 mg/kg/d) every day or fluconazole 0.89
(impregnation, 12 mg/kg/d; followed by 6 mg/kg/day) every day for all patients.
Breast-feeding should be suspended until there is certainty of the maternal status with respect to CMV infection. Breast-feeding 0.88
will be contraindicated in every mother who can transmit CMV. (If it is not possible to perform these examinations in a timely
manner, it will be preferable to suspend breast-feeding and feed with milk formula.)
Patients who have been vaccinated with BCG (regardless of symptomatology) should receive antimycobacterial drugs. 0.82
Use of pyrazinamide should be avoided as part of the antimycobacterial treatment of those patients who have received the BCG 0.83
vaccine (Mycobacterium bovis) because of the intrinsic resistance of the microorganism.
Patients who have been vaccinated with BCG and who have BCGitis should receive 0.82
rifampicin 1 ethambutol 1 isoniazid 1 clarithromycin.
Patients who have been vaccinated with BCG and who have BCGosis should receive 1.00
rifampicin 1 ethambutol 1 isoniazid 1 clarithromycin.
3. Treatment with IVIG, SCIG, or both
Replacement treatment with human immunoglobulin should be started immediately in all patients. 1.00
The first dose of human immunoglobulin should always be administered intravenously. 0.89
The minimum substitutive IVIG dose should be 400-600 mg/kg/d every 3 to 4 weeks. 1.00
The minimum substitutive SCIG dose is 100-200 mg/kg/d every 1 to 2 weeks. 0.82
Additional doses of human immunoglobulin should be administered during active infections. 0.77
The serum concentration of IgG must be monitored to modify the treatment dose. 0.88
(Continued)
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TABLE I. (Continued)
Intervention Kappa value

4. Application of immunization
In newborns with suspected or diagnosed SCID, it must be reported in the patient’s file and cradle (eg, on a sign) that BCG 1.00
vaccine should NOT be applied for any reason.
The complete vaccination scheme should be ensured/corroborated in all adults who have close contact with patients with SCID. 0.93
Application of vaccines derived from live attenuated microorganisms (ie, BCG, rotavirus, varicella, measles, rubella, parotitis, 0.94
yellow fever, typhoid fever, cholera, oral polio, and intranasal influenza) is contraindicated in patients with SCID.
Application of vaccines derived from live attenuated microorganisms (ie, BCG, rotavirus, varicella, measles, rubella, mumps, 0.83
yellow fever, typhoid fever, cholera, oral polio, and intranasal influenza) is contraindicated in close relatives of patients.
Application of all vaccines that are not attenuated live microorganisms should be ensured in close relatives of the patients. 0.88
The influenza vaccine should be applied annually to all close relatives, as well as medical and paramedical personnel who have 1.00
contact with patients with SCID.
5. Dietary and nutritional aspects
In case of suspension of breast-feeding, feeding should be provided with formula prepared under sterile conditions. 1.00
All patients should be evaluated by gastroenterology and nutrition specialists to establish an intensive nutritional plan 0.83
(considering even total or mixed parenteral nutrition or nutrition by means of an orogastric/nasogastric tube).
The ideal formula to administer will obey clinical conditions (starting with formula according to age), and only in the case of 0.94
specific symptoms will some specialized formula be selected.
Somatometry (weight, height, and head circumference) should be evaluated weekly in all patients. 0.82
The diets of ablated patients should be low in bacteria and/or sterile. 1.00
Avoid storage of food in the rooms of patients with SCID. 1.00
6. Antimicrobial treatment
Given the suspicion of an infectious process, broad-spectrum empiric antimicrobial treatment (covering gram-positive, 0.82
gram-negative, mycobacterial, fungal, and viral agents) should be initiated in all patients.
Appropriate initial empiric antimicrobial treatment of a suspected infectious process in patients with SCID should include 0.88
coverage for gram-positive and gram-negative organisms (eg, third-generation cephalosporin).
In patients with a suspected infectious process, the infectious focus and microorganism responsible for directing treatment should >0.75
be exhaustively searched through the following studies:
d complete blood count with differential;
d urine test for bacteria, fungi, and mycobacteria;
d stool test;
d CMV viral load;
d EBV viral load; and
d thoracic radiography.

In patients with a suspected infectious process, fungal forms should be looked for in urine. 0.77
In patients with a suspected infectious process, fungal forms should be looked for in nail, mouth, and skin lesions. 0.88
In patients with a suspected infectious process, Candida species antigen should be looked for in blood. 0.77
In patients with a suspected infectious process, Aspergillus species antigen should be looked for in blood. 0.77
In patients with a suspected infectious process, PCR should be performed for mycobacteria. 0.82
In patients with a suspected infectious process, acid-resistant bacteria should be sought with Ziehl-Neelsen stain in gastric juice. 0.75
In patients with a suspected infectious process, an ophthalmologic evaluation should be performed to rule out infectious 0.9
processes at this level.
In patients with a suspected infectious process, abdominal ultrasonography should be performed (eg, search for fungomas, 0.82
abscesses, and collections).
In patients with SCID younger than 6 months of age who present with fever without an identified infectious focus, lumbar 0.9
puncture should be performed.
Bronchoscopy and bronchoalveolar lavage should be performed only in the case of respiratory symptoms. 0.77
Echocardiography should be performed in patients with SCID who present with fever without an obvious focus. 0.82
When there is information about an involved microorganism, antimicrobial coverage should be adjusted without suspension of 0.88
habitual prophylaxis.
If already started, empiric treatment with ganciclovir will be suspended once there is a negative viral load for CMV. 0.88
If CMV infection is confirmed (ie, positive viral load), treatment should be continued for 14 days after symptoms are resolved 0.77
and a negative CMV viral load result is determined by using PCR.
7. Use of blood products
All blood products must be negative for CMV serology, leuko-reduced, and irradiated to eliminate the risk of graft-versus-host 1.00
disease and CMV infection.
Use of blood products should be limited to situations that place the lives of these patients at risk. 0.83

(Continued)
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TABLE I. (Continued)
Intervention Kappa value
8. Routine laboratory tests
Laboratory tests that should be requested for ALL patients at the time the patient is classified with SCID or probable SCID, when >0.75
available, are as follows:
1 1 1 1 1
d lymphocyte subsets (CD3 , CD4 , CD8 , CD16 /561, CD19 );
d studies of lymphoproliferation with different stimuli (phorbol 12-myristate 13-acetate, PHA, and anti-CD3/CD28);
d viral load for CMV and EBV;
d Immunoglobulins (IgG, IgM, IgA, and IgE);
d TCR diversity studies; and
d thymic ultrasonography.

T-lymphocyte subsets (CD45RA1 and CD45RO1) should be measured only in the case of lymphocytes present in blood counts 0.75
or on flow cytometry.
Conduct studies to evaluate the TCR diversity in patients with SCID. 0.75
Radiosensitivity tests should be performed in all patients with microcephaly (under suspicion or a diagnosis of SCID). 0.82
Radiosensitivity tests should be performed in all patients with microcephaly and a T-B- immunophenotype. 0.93
Studies to determine maternal graft or previous transfusion graft (CD31CD45RA1 and CD31D45RO1/karyotype/determination 0.75
of chimerism by HLA) should be performed only in patients with symptoms of graft-versus-host disease.
TREC quantitative analysis should be performed in ALL patients at the time the patient is classified with SCID or probable 0.77
SCID.
Search for mycobacteria should be performed in all patients who have received the BCG vaccine (Ziehl-Neelsen stains, PCR in 0.82
the corresponding fluids, and staining in biopsy specimens).
Biopsy of any obvious skin lesion should be performed (in addition to light microscopy, request stains for fungi and mycobacteria 0.77
and send tissue to culture for bacteria, fungi, and mycobacteria).
Multiorgan functional evaluation (ie, complete blood count with differential, liver function tests, blood chemistry, serum 0.87
electrolytes, and general urinalysis) should be part of the blood tests requested should be performed for ALL patients at the time
the patient is classified with SCID or probable SCID.
Save a blood sample on filter paper for all patients with SCID before carrying out any type of transfusion. 0.82
Save samples of genetic material from both the patient and both parents when possible. 1.00
Request HLA studies of the patient and immediate family members from the moment the diagnosis is confirmed. 1.00
Request the viral load for HIV in all patients. 0.93
9. Imaging and other studies
Perform chest radiography in all patients (evaluate parenchyma, infiltrates, and bone changes and the presence or absence of 0.94
thymic shadow).
Perform high-resolution lung computed tomographic scans in all patients who present or have presented with respiratory 0.93
symptoms to determine the presence and/or extent of lung damage.
Imaging studies involving ionizing radiation should be minimized in patients with the T-B- immunophenotype (unless 1.00
radiosensitivity has been ruled out).
Perform auditory and visual screening in all patients with SCID. 0.82
Perform bone marrow aspiration in all patients with SCID and suspicion of reticular dysgenesis. 0.77
10. Protocol evaluations
Request early consultation and assessment for specialists as follows: >0.75
d immunology;
d transplantation of hematopoietic progenitor cells;
d infectious diseases;
d gastroenterology;
d nutrition;
d psychology;
d genetics;
d neurology;
d rehabilitation;
d hematology;
d ophthalmology; and
d cardiology.

Notify and request early assessment of critical care specialists (even when the patient is stable) and establish intrahospital 0.87
programs that ensure immediate access of patients with SCID to critical care areas, as needed.
Notify blood bank directly about admission of patients with suspicion or a diagnosis of SCID to the hospital. 0.93
Ensure early intervention of social support services in conjunction with the medical team. 1.00
Always request a postmortem study in all patients with SCID who die. 0.87
Perform and append the pedigree chart of all patients with SCID, with a minimum of 3 generations. 1.00
Implement a special data collection sheet for patients with SCID in the clinical file. 0.87
CMV, Cytomegalovirus; IVIG, intravenous immunoglobulin; SCIG, subcutaneous immunoglobulin; TCR, T-cell receptor; TMP/SMX, trimethoprim-sulfamethoxazole; TREC, T-cell
receptor DNA excision circle.
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identified newborns with SCID had infections before To our knowledge, this is the first document trying to
transplantation, among whom 76% were acquired in the period standardize supportive treatment in patients with SCID. The
between the confirmation of diagnosis and the performance of interventions should be implemented from the moment there is
HSCT.21 All the above reflects the complexity of these diseases suspicion of an SCID diagnosis to reduce the risk of
and the need to establish strategies that improve the prognosis complications. Although consensus is based on the perspectives
of patients with SCID. of Latin American clinicians, this document will also serve as a
Based on available information, we developed an initial guide in other parts of the world mainly but not exclusively in
document with diagnostic and therapeutic interventions for places where neonatal screening for SCID is not yet available. In
patients with SCID to be submitted for evaluation by qualified the near future, we are planning to spread the consensus among
SCID experts. We divided supportive measures into 10 main the most significant possible number of primary care physicians
domains (Fig 3). and specialists through the network of immunologists belonging
The expert panel was composed of 34 clinicians (30 clinical to PID societies (the Latin American Society for Primary
immunologists and 4 infectious disease specialists) from 6 Immunodeficiencies, Clinical Immunology Society, and
countries (Argentina, n 5 4; Brazil, n 5 5; Chile, n 5 3; Costa European Society for Immunodeficiencies among others) and
Rica, n 5 2; Mexico, n 5 19; and Peru, n 5 1). We carried out a through its publication in English and Spanish. We will develop a
consensus under the Delphi-modified technique electronically user-friendly format as an intervention checklist for supportive
and anonymously by using the Google Forms platform and used measures and as an electronic tool to facilitate sharing of
Microsoft Excel to register and analyze data. Each of the information and clinical implementation.
interventions was analyzed successively until a ‘‘consensus’’ We also present the interventions that did not reach a consensus
criterion defined by a kappa concordance index among experts of in Table E1, and it is noteworthy to mention that besides the lack
0.75 or greater or ‘‘no consensus’’ when a kappa value of less than of consensus, these interventions must be revised, and many of
0.75 was reached. We measured stability of responses between them might be considered in particular clinical scenarios. Also,
rounds using repeated-measures ANOVA, and we stopped the they represent gray areas for clinical care, where more discussion
consensus when the P value was greater than .05. Finally, we and evidence are needed.
asked the experts to present their arguments in favor or against The authors know that SCID management decisions are
the ‘‘no consensus’’ interventions to provide relevant information complex and depend on many factors, including local experience,
for clinicians to use this document. the patient family’s preferences, available resources, and
After 3 rounds of consensus (Fig 4),22 we gathered a final institutional policies. This consensus might help improve
document, which is presented here (Table I), including 123 outcomes for patients with SCID and represents a guideline that
interventions that achieved consensus and therefore should be can be adapted and implemented in the different centers facing
implemented in every patient with SCID as soon as the diagnosis SCID. It also represents a joint effort of clinicians belonging to the
is suspected. Another 38 interventions did not reach consensus Latin American Society for Primary Immunodeficiencies and the
and are presented in Table E1 in this article’s Online Repository commitment of that society to improve the diagnosis and
at www.jacionline.org. treatment of patients with PID.

We acknowledge the PID experts who helped us during the first phase of this
DISCUSSION AND RECOMMENDATIONS work and kindly provided input and comments about clinical practices in their
The time elapsed from SCID diagnosis until the completion of centers: Kathleen Sullivan, Luigi Notarangelo, Jordan Orange, Richard
definitive treatment is essential because appropriate interventions Stiehm, Chaim Roifman, Jean-Laurent Casanova, Anders Fasth, and Cristoph
can prevent complications. We found that no evidence-based Klein. We also want to acknowledge the Latin American Society for Primary
clinical guidelines exist on the supportive treatment for patients Immunodeficiencies and Fundaci
on Mexicana para Ni~nas y Ni~nos con
with SCID, and the creation of a document allowing the Inmunodeficiencias Primarias A.C. (FUMENI) for their support in this work.
establishment of sequential guidelines for patients with a
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