Brief clinical and laboratory observation

Prevalence of Pneumocystis carinii pneumonitis in severe combined immunodeficiency1

Pneumocystis jirovecii pneumonia (PJP) is a life-threatening condition in immunocompromised children. Our aim is to analyze the epidemiologic and clinical characteristics of PJP cases in our setting, describing the prognosis and related risk factors.

Retrospective study including all pediatric patients (≤18 years) with PJP admitted to our hospital (January 1989–December 2016). Case definition: patient with acute pneumonitis and P. jirovecii detection in bronchoalveolar lavage or tracheal aspirate using methenamine silver or direct antibody fluorescence staining, or Real-Time Polymerase Chain Reaction.

Twenty-five cases (0.9 cases/year) were identified. Median age was 2.2 years (interquartile range: 0.5–12.3), 64% were male, and 12% were receiving appropriate antimicrobial prophylaxis. Cytomegalovirus coinfection was detected in 26% cases. The most common underlying diseases were primary immunodeficiencies (36%) and 16% were human immunodeficiency virus (HIV)-infected children. Eighteen were admitted to the pediatric intensive care unit (PICU) and overall 30-day mortality was 20% (31.25% in HIV non-infected vs 0% in HIV-infected patients; OR: 0.33, 95% CI: 0.02–7.24, p = 0.55). Clinical outcome was worse in girls and those patients requiring adjuvant steroid therapy. HIV non-infected patients, higher initial LDH, younger age and shorter time elapsed between diagnosis of PJP and the underlying disease were identified as risk factors to be admitted to the PICU (p = 0.05, p = 0.026, p = 0.04 and p = 0.001 respectively).

Accompanying the widespread use of combined antiretroviral therapy, PJP has been diagnosed almost exclusively in HIV non-infected children at our institution. Moreover, significant higher morbidity rates associated with PJP are seen in this group of patients.

La neumonía por Pneumocystis jirovecii (PJP) es una enfermedad potencialmente letal en niños inmunocomprometidos. Nuestro objetivo es analizar las características epidemiológicas y clínicas de la PJP, describiendo el pronóstico y los factores de riesgo.

Estudio retrospectivo (enero 1989-diciembre 2016) de pacientes pediátricos (≤18 años) con PJP. Definición de caso: paciente con neumonitis aguda y detección de P. jirovecii en lavado broncolaveolar o aspirado traqueal usando tinción con plata-metenamina o inmunofluorescencia directa, o reacción en cadena de polimerasa en tiempo real.

Se identificaron veinticinco casos (0,9 casos/año); edad mediana: 2,2 años (rango intercuartílico: 0,5-12,3), 64% de sexo masculino, y 12% bajo profilaxis anti-PJP. La coinfección por citomegalovirus se demostró en el 26%. Las enfermedades subyacentes más frecuentes fueron las inmunodeficiencias primarias (36%) y el 16% estaban infectados por el VIH. Dieciocho ingresaron en Cuidados Intensivos Pediátricos (UCIP) y la mortalidad global a los 30 días fue del 20% (31,25% en VIH- vs 0% VIH + ; OR: 0,33 95%CI 0,02-7,24 p = 0,55). El pronóstico fue peor en niñas y en aquellos que recibieron tratamiento adyuvante con corticoides. Se identificaron como factores de riesgo para ingreso en UCIP la ausencia de infección por VIH, valores iniciales elevados de LDH, menor edad y un período más corto entre el diagnóstico de PJP y la enfermedad subyacente (p = 0,05, p = 0,026, p = 0,04 y p = 0,001, respectivamente).

Tras la aplicación generalizada de la terapia antirretroviral, la PJP se diagnostica casi exclusivamente en niños no infectados por el VIH en los que, además, se identificó una mayor morbilidad.

Severe combined immunodeficiency disease (SCID) refers to a heterogeneous group of rare (1/100,000 live births), lethal, congenital disorders that result in the inability of T cells to respond to mitogens, alloantigens, and specific antigens and B cells to produce specific antibodies.¹ Before the early 1990s, patients with this disorder were characterized primarily by the phenotype and function of their circulating lymphocytes, mode of inheritance, and presence or absence of enzyme deficiencies known to be associated with SCID, such as adenosine deaminase. In this original classification, three main types of SCID were described² and include the following: (1) classical SCID, characterized by T and B lymphopenia, with or without natural killer (NK) cells, and agammaglobulinemia, (2) the more common SCID with B lymphocytes, and (3) SCID secondary to adenosine deaminase (ADA) deficiency, which may present with either of the preceding lymphoid phenotypes.3, 4 Less often, children with SCID present with Omenn's syndrome,⁵ in which affected infants have scaling erythroderma, leukocytosis, eosinophilia, hepatosplenomegaly, and lymphadenopathy with replacement of nodal architecture by Langerhans and reticulum cells,⁶ reticular dysgenesis,⁷ in which SCID is associated with severe neutropenia and often bilateral sensorineural deafness,⁸ or SCID with short-limbed dwarfism and ectodermal dysplasia.⁹ Multiple variants of SCID have been described in which patients have nonfunctional T cells that demonstrate capping defects,¹⁰ lack CD7¹¹ or possess abnormal CD3 subunit expression,¹² or have CD8 deficiency with nonfunctional CD4⁺ cells.13, 14 Despite this phenotypic heterogeneity, the distribution of SCID phenotypes reported in four separate studies performed in Europe and the United States was surprisingly similar.15, 16, 17, 18 Approximately 40% of patients presented as SCID with B cells, 25% as classical SCIDs (B⁻T⁻), 15% with ADA deficiency, 10% as SCIDs with nonfunctional T cells, and 2% to 3% with reticular dysgenesis. Inheritance of these disorders are either autosomal recessive (ADA deficiency,4, 19 short-limbed dwarfism,⁹ Omenn's syndrome,⁵ capping defects,¹⁰ CD8 deficiency,13, 14 or as either an X-linked or autosomal recessive disorder (classical SCID, SCID with B cells, reticular dysgenesis).14, 20

Although first trimester diagnosis of adenosine deaminase deficiency has been possible for many years by measurement of enzyme activity in cultured amniocytes or chorionic villi samples,²¹ children with ADA⁺ SCID, until recently, required fetal blood sampling to ascertain the presence or absence of T cells.²² The elucidation of many of the genetic mutations which give rise to SCID, such as X-linked SCID (IL-2R gamma chain),23, 24, 25 autosomal recessive SCID with B cells (JAK-3),26, 27 classic SCID, Omenn's syndrome28, 29, 30, 31 (recombinase defects (RAG-1, RAG-2), and CD8 deficiency with nonfunctional T-cells (ZAP-70),32, 33, 34 has increased the proportion of infants who can be diagnosed by amniocentesis or chorionic villus sampling (CVS).35, 36 Better prenatal diagnosis, earlier postnatal diagnosis, because of heightened awareness of immunodeficiency disorders resulting from the AIDS epidemic, in conjunction with advances in anti-microbial therapy, have reduced the number of children presenting to bone marrow transplant (BMT) with a life-threatening infection.

Successful correction of SCID by BMT was first reported by Gatti et al using bone marrow derived from an HLA-matched sibling.³⁷ Since that report, over 500 curative transplants for this disorder have been performed,³⁸ the majority using T-cell–depleted haploidentical parental bone marrow. Within the last 5 years, advances in unrelated bone marrow³⁹ and cord blood transplantation⁴⁰ and successes with in utero stem cell transplants⁴¹ have expanded the options available to infants with SCID, particularly those lacking an HLA-matched sibling. In this article, the results and continued controversies of stem cell transplantation for SCID are reviewed.

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV), frequently found in the acquired immune deficiency syndrome (AIDS), have been suspected of contributing to the latter immunodeficiency. The ability of normal HLA-identical sibling bone marrow to reconstitute an 8-month-old infant with severe combined immunodeficiency infected with these two viral agents is of interest. After presentation with severe mucocutaneous candidiasis, cavitary pulmonary disease, nodular cutaneous lesions, and hepatic abscesses containing acid-fast organisms, immunologic studies revealed lymphopenia. 1–3% T cells, and no lymphocyte responses to mitogens. Prior to transplantation, the infant's blood B lymphocytes grew spontaneously in culture, suggesting they were infected with EBV. Indeed, an appropriate antibody response to EBV was detected at 2 months post-transplantation. At 3 weeks postgrafting, neutropenia and cholestatic jaundice developed without other signs of graft versus host disease. Liver biopsy demonstrated CMV but no EBV by DNA hybridization. There was evidence of T- and B-cell function by 2 weeks postgrafting, including vigorous in vivo and in vitro responses to candida. Although the blood lymphocyte T4:T8 ratio was inverted at 2 weeks, it reverted to normal by 6 weeks post-transplantation. All clinical disease resolved by 8 months and karotyping revealed all T and B lymphocytes to be XX. Thus, despite infections with both CMV and EBV, complete immunologic reconstitution was achieved in this, the most severe of all genetically determined immunodeficiency conditions, arguing against these viruses having a major role in the failure of bone marrow transplantation in AIDS.