Severe Chronic Neutropenia

D.C. Dale, K. Welte, "Severe Chronic Neutropenia - The Role of Haematopoietic growth factors", 1993

Clinical Problems Associated With Severe Chronic Neutropenia

(i) Increased Susceptibility to Infections

Neutrophils serve as the first line of defence to bacterial infections when any break in the cutaneous and mucosal barriers occurs. The ability to mount a neutrophilic response depends upon the tissue vascular supply, the number of available cells and their function. The frequency and severity of clinical infections can usually be related to the size, type and circumstances of bacterial inoculum, the available neutrophil supply, personal hygiene and a few other factors. In patients with severe chronic neutropenia, the capacity to mount a mononuclear cell response is generally intact. This means that although the first wave of host defences may be inadequate, there is often an adequate second stage or delayed response to prevent bacteraemia. The net result is many fevers and acute symptoms, common problems with chronic inflammatory processes and slow healing of severe infections.

Although these general principles apply well to all forms of severe chronic neutropenia, the observed frequency of bacterial infections and other clinical problems varies substantially from patient to patient and across these symptoms. Some patients tend to have recurrent problems and others do remarkably well. Age is an important factor, children having more problems than adults. There is a slight male predominance in the incidence of congenital neutropenia and female predominance in chronic idiopathic neutropenia, but the clinical problems observed in both males and females are similar. There is no clear correlation of the total white blood cell count versus the neutrophil count and the occurrence of infections, although many clinicians have the impression that patients with higher white blood cells, reflecting higher lymphocyte, monocyte and eosinophil counts do somewhat better.

(A) Pattern of infection in cyclic neutropenia

In patients with cyclic neutropenia there is a very predictable pattern of oral ulcers, cervical lymphadenopaghy and painful gingivitis every three weeks coinciding with the neutropenic periods. Fever, evidence of sinusitis, otitis media, pharyngitis and bronchitis are somewhat less common. Episodes of abdominal pain, perianal ulceration, cutaneous cellulitis and abscess formation will often occur several times per year. Bacteraemia is a very rare but frequently fatal event. Thus, these patients have very predictable patterns of symptoms but there is considerable variation between patients and in the same patient over time. The reasons for this variation are poorly understood but may relate to variations in the duration of neutropenia with each cycle, or in other aspects of the host defense system.

(B) Pattern of infection in congenital neutropenia

In severe congenital neutropenia the sites of primary symptoms are similar to cyclic neutropenia with the same predilection to oral and gastrointestinal ulceration. In these patients, however, there is no recovery period of neutrophils, as occurs in cyclic neutropenia, and they are therefore much more prone to deeper invasion by bacteria with chronic pneumonia, deep abscesses in muscle, liver and other tissues. Fever is common, but bacteraemia is quite infrequent. They tend to have chronic infections, particularly in early childhood, which heal very slowly despite optimal supportive measures and antibiotics.

(C) Pattern of infection in idiopathic neutropenia

Patients with chronic idiopathic neutropenia may be relatively well except for periodic episodes of fever, oral and upper respiratory symptoms, and occasional episodes of lower respiratory tract symptoms which persist much longer than in haematologically normal individuals. There is considerable clinical variation within this group, including the pattern of response to infection. In some of these patients it appears that the occurrence of infection stimulates neutrophil production in a delayed fashion, with transient rising counts followed by recurrence of severe neutropenia after the event has resolved.

(D) Causative organisms

Infections in patients with severe chronic neutropenia are usually caused by surface organisms. If antibiotic exposure is minimized, these organisms tend to be sensitive to antibiotics. In the oropharyngeal cavities it is difficult to identify the causative organisms precisely, but streptococcal species and anaerobic organisms normally are the dominant pathogens. Cutaneous infections are usually caused by Staphylococcus aureus and streptococci, except in the perianal area, where Gram-negative anaerobic organisms are often implicated. Patients with cyclic neutropenia have an unusual predilection to developing bacteraemia by Clostridium species, presumably because of their close association with the epithelial surfaces from which they can gain access to the blood during the neutropenic periods.

(ii) Oropharyngeal disease

Gingivitis, periodontal disease and the loss of permanent teeth is a common problem across the spectrum of neutropenic syndromes. These problems can be attributed to a failure in the natural function of neutrophils which normally migrate to the gingival crypts where bacteria tend to proliferate. Good oral hygiene is extremely important but it is difficult to maintain. Many cases of severe chronic neutropenia are diagnosed because of dental problems.

(iii) Morbidity and mortality

It is difficult to establish the morbidity and mortality rates for severe chronic neutropenia precisely because of the rarity of the condition and problems in medical record-keeping. Nevertheless, it is apparent that almost all patients with persisting counts of less than 0.5 x 109 /L blood neutrophils have significant problems with gingivitis and increased periodontal disease, despite good efforts at oral hygiene. Recurrent fevers and symptoms sufficiently severe to require antibiotics occur in severe congenital neutropenic children as frequently as once or twice a month, and many of these patients receive chronic and continuous antibiotic treatment. Most patients with cyclic neutropenia are symptomatic with each neutropenic period, sufficiently so that school or work absenteeism are common at three week intervals. In idiopathic neutropenia, patients with the lowest counts have the most frequent problems; some patients have fever and symptoms suggesting a severe and septic illness several times per year. In other milder cases, symptoms occur far less frequently.

Although there are no precise figures available, the mortality rates of severe chronic neutropenia have undoubtedly diminished and much older patients with severe chronic neutropenia are now being reported compared with 30 years ago. The availability of improved antibiotic therapy, especially oral antibiotic therapy, has helped to prevent deaths from severe infections. Most case reports from before 1960 describe a fatal outcome, whereas there are many patients who have now lived into early adulthood with well documented congenital neutropenia.

In cyclic neutropenia, deaths from clostridial bacteraemia have been reported for several isolated cases and also observed in family studies.

Patterns of hospitalizations and the use of specific antibiotics and other treatments have varied considerably, depending upon the experience and views of the patient’s physician and local hospitalization practices. In general, there has been a tendency to hospitalize these patients less frequently as the syndromes causing severe chronic neutropenia are better understood and oral antibiotics have improved. The greatest problems with life-threatening infections and prolonged hospitalizations are for very young children, for whom an impaired neutrophil response portends a high fatality rate even under the best circumstances.

(iv) Quality of Life

The life of the patient with severe chronic neutropenia is severely impacted by chronic oropharyngeal inflammation and recurrent skin and soft tissue infections and, for more severely affected individuals, repeated and chronic hospitalizations for treatment of fever and deep tissue infections. For essentially all patients, despite antibiotic treatments, recurring episodes of fever and illness with absenteeism from work and school, are chronic problems. There are major impacts on social and geographic mobility and difficulties with completing education and obtaining secure employment. For the family of a patient with chronic neutropenia, much time is spent providing care and making decisions regarding the need to seek medical attention.