TL Lee, GCF Chan, SY Ha, YL Lau

Abstract

A total of 99 cases of primary immunodeficiency diseases (PID) (61 males, 38 females) were registered at the Paediatric Immunology Clinic, Queen Mary Hospital, University of Hong Kong between July, 1988 and December, 1998. The following frequencies were found: predominantly humoral defects (n=34); predominantly T cell defects (n=15); combined immunodeficiency (n=5); phagocytic disorders (n=35); others (n=10). Chronic neutropenia was the most frequent disorder (n= 19), followed by X-linked agammaglobulinemia (n= 12), chronic granulomatous disease (n=12), selective deficiency of IgG subclass (n=10), common variable immunodeficiency (n=7), Wiskott-Aldrich syndrome (n=6) and severe combined immunodeficiency (n=5). Infection was the major complication leading to mortality (n=6). Lymphoma developed in 3 patients. Bone marrow transplantation was done in 12 patients with over 90% success rate. The clinical approach and general principles of management of PIDs will also be discussed.

Introduction

Primary immunodeficiencies are a group of diseases characterized by an unusual susceptibility to infection. Although previously considered a rare pathology,¹ in the past few years, primary immunodeficiency diseases (PID) have been increasingly recognized, due to advances in the understanding of immune system and recent progress in immunological and molecular techniques. As a result of these advances, better diagnosis and more effective therapy have been achieved. Primary immunodeficiencies are relatively rare and very few data exist regarding the true incidence. From countries where primary immunodeficiency registries were established (Sweden, Australia and Japan), the incidences of various primary immunodeficiencies have been estimated. The overall incidence of significant symptomatic antibody deficiency was between 1 in 8,000 to 1 in 11,000 livebirths, and that of severe combined immunodeficiency was 1 in 70,000 live births. The incidence of granulocyte deficiencies was estimated to be 1 in 15,000 livebirths. Complement deficiencies are comparatively rare and may result in either autoimmune diseases or recurrent infections, mainly due to meningococci. Collectively, the overall incidence of PID is about 1 in 5,000 live births² based on PID registries in Japan,³ Sweden⁴ and Australia. These represent minimal incidences since many more cases would have gone undiagnosed. Epidemiological data on rare disorders contribute significantly to our understanding of the disease.

Patients and Methods

A total of 99 patients with the diagnosis of PID were registered during the period from July, 1988 to Dec, 1998. PID was diagnosed according to WHO criteria. The patients were referred from other public hospitals and private sectors. Only patients with well-established immunodeficiencies and clinical manifestations were included and they were reviewed retrospectively from the medical records from the Department of Paediatrics of Queen Mary Hospital.

Laboratory analysis included blood smear, immunoglobulins, isohaemagglutinins, antipoliovirus and antihepatitis B virus antibodies, nitro-blue tetrazolium test (NBT), and haemolytic titration of complement (CH50) and Factor B. If indicated, the evaluation of immunocompetence was extended to IgG subclasses, antibody responses to vaccine antigens, lymphocyte subpopulations, proliferation of T cells to mitogens, natural killer cell function test, T and B cell function, antineutrophil antibody test, CD-40 ligand assay, T-cell receptor rearrangement, cytokines profile, chemotaxis, phagocytosis, and bactericidal activity.

Result

In Table I, the relative frequencies of primary immunodeficiency disorders in children at our clinic compared to other reports are presented. The detailed diagnosis, sex distribution, and mortality rate are presented in Table II. The male-to-female ratio is 1.6 to 1. During the observation period, 6 of 99 children died. With 99 cases of PID over 10.5 years, the overall minimum incidence of PID in Hong Kong was estimated to be about 1 in 8,000 livebirths. Twelve had undergone bone marrow transplantation^5-6 with 92% success rate (Table III, IV).

Infections were the major complications causing significant morbidity and mortality. Lymphoma developed in 3 of the 99 patients, who were suffering from Wiskott-Aldrich syndrome (large B cell lymphoma), ataxia telangiectasia (centroblastic B-cell lymphoma) and common variable immunodeficiency (low grade Mucosa Associated Lymphoid Tissue [MALT] B cell lymphoma) respectively. They were treated with chemotherapy of reduced doses and achieved remission.

For those 6 deceased patients, 3 patients with chronic granulomatous disease died of Chromobacterium septicaemia (n=l), E. coli septicaemia (n=1), and disseminated Pseudomonas infection (n=1) respectively. One patient with leukocyte adhesion deficiency type 1 died of disseminated atypical mycobacterial infection, one with ataxia telangiectaxia died of end-stage bronchiectasis and one with complete DiGeorge syndrome died of severe interstitial pneumonitis in the early phase after bone marrow transplant.

Discussions

The demographic data, relative distributions of different subtypes, major complications and treatment outcomes of primary immunodeficiency diseases are reviewed in this report. It should be pointed out that, according to the incidences of PID in different countries (including Asian and Western countries), the present reported incidence (about 1 in 8000 livebirths) of PID in Hong Kong is the minimum incidence which is lower than the true incidence. However, with increased awareness of primary immunodeficiencies among paediatricians as well as the availability of laboratory investigations, there shall be more children being diagnosed in the future, not only for optimal treatment but also for genetic counseling.^7-9 Therefore setting up a primary immunodeficiency registry will help to ascertain more exactly the incidence rate and focus on the needs of this group of patients.

A child with PID usually presents with recurrent infectious but the majority of children with recurrent infection do not have PID. A normal child may have eight to ten respiratory infections per year, especially if he has elder sibs or just encounters a major life event, for example moving into a new neighborhood or entering the nursery. Parents of such children can usually be reassured confidently as long as the growth is normal and there are no end-organ damage such as perforated eardrums, skin scarring due to abscesses, chronic sinusitis, or lower respiratory tract involvement such as bronchiectasis. If respiratory symptoms are the only "infectious" manifestations, allergic disorders such as asthma and allergic rhinitis have to be considered first. In Caucasians, cystic fibrosis has to be excluded early but it is extremely rare in Southern Chinese in Hong Kong. For recurrent infections that are localized to one anatomical site, structural defect is the most likely cause. For example, middle ear or mid-line defects and basal skull fracture may be the cause for recurrent meningitis and coronal thin-section cranial computed tomography may be the investigation of choice to delineate anatomic defects. Likewise, recurrent pneumonia involving always the same lobe should point to either a foreign body or anatomical defect, mandating bronchoscopy as the first line of investigation rather than assessing the immune function. Secondary immunodeficiencies such as malnutrition, prematurity, splenectomy and malignancy also outnumber PID. Only after careful consideration of the above causes and one still cannot find a reason for the recurrent infections, PID then has to be considered.

History suspicious of PID includes consanguinity of parents,¹⁰ early deaths of relatives from sepsis and unusual reactions to live vaccines such as BCG and oral polio vaccine. The infectious history may reveal increased frequency, unusual severity, prolonged course, and unexpected complications even on adequate anti-microbials and early relapse of the original infection on stopping the anti-microbials.^11-15 PJD may also be associated with collagen-vascular diseases.¹⁶

Physical examination should be directed for evidence of end-organ damage such as perforated or scarred eardrums due to repeated otitis media, scarred skin due to healed skin abscesses, bronchiectasis due to recurrent pneumonia and refractory oral and cutaneous candidiasis. Growth may be stunted as well. It is also useful to recognize "patterns" of certain specific PID. (Table V)

Detailed documentation of infections is important because the age of onset, types of pathogens involved and sites of infection may lend clues to which arm of the immunity may be defective. (Table VI)

For vaccination, killed vaccine (e.g. inactivated poliomyelitis vaccine) should be given if there is evidence of some antibody synthesis. Live attenuated vaccines (e.g. live oral poliomyelitis vaccine, BCG) should be avoided in all severe antibody or cellular immunodeficiencies to avoid the risk of vaccine-induced infection. Live oral poliomyelitis vaccine (OPV) should not be given to their parents, siblings, and other household members as the patient may contract paralytic polio from live OPV. Varicella-Zoster immunoglobulin (VZIG) is indicated for T-cell and antibody deficient children following recent chickenpox exposure.

For patients with cellular immunodeficiencies, blood products including packed red cells and platelets concentrate should be irradiated prior to administration to prevent graft-versus-host reaction from heterologous lymphocytes. Because of the risk of cytomegalovirus (CMV) infection from blood products, it is advisable to use CMV-negative or high efficiency leukocyte filtered products.

One of the mainstays of management in most immunodeficient patients is the use of antibiotics given either in response to infection or on a long-term prophylactic basis. These patients may succumb rapidly to infection, therefore fevers or other manifestations of infection are assumed to be secondary to bacterial infection, and antibiotics treatment should be started immediately. Pneumocystis carinii pneumonia (PCP) prophylaxis is recommended for children with significant T-cell immunodeficiencies. Alternative drugs for PCP prophylaxis include pentamidine and dapsone.

Continuous prophylactic antibiotics are often beneficial in certain immunodeficiencies. They are especially useful in disorders characterized by rapid overwhelming infections such as Wiskott-Aldrich syndrome, in antibody immunodeficiencies when recurrent infections still occur despite optimal immunoglobulin therapy, and in certain phagocytic disorders such as chronic granulomatous disease.

Antiviral therapy is useful for certain viral infections. Severe infections due to herpes simplex virus (HSV), or varicella zoster virus (VZV) can be treated with acyclovir. Acyclovir resistant strains of HSV can be controlled by foscarnet while CMV by ganciclovir. Intravenous immunoglobulin is indicated in the management of several primary immunodeficiencies as shown in Table VII.

Primary immunodeficiencies that are potentially fatal are candidate diseases for BMT. However, because the procedure may be associated with immediate mortality, the risk: benefit ratio has to be carefully assessed. Theoretically, if the PID is a result of defects that are intrinsic to cells of one or more haematopoietic lineages, it is correctable by BMT. The majority of transplants have been performed in patients with severe combined immunodeficiency (SCID) or Wiskott-Aldrich syndrome (WAS).

In conclusion, PID is relatively rare but early and accurate diagnosis is of utmost importance for starting specific management plan.^17-18 This will benefit individual patients with PID as well as offering genetic counseling including prenatal diagnosis to the parents, furthermore, even in-utero treatment may be possible.¹⁹ A primary immunodeficiency registry should be set up in Hong Kong for better documentation of this group of rare diseases.

Acknowledgment

We sincerely thank all the paediatricians for referring and sharing the care of their patients with us as well as the Immunology Laboratory in Queen Mary Hospital for their help in investigating our patients.

References

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