The earliest published report of CGD in Malaysia as case reports was in 1994 compared to India in 1999, Taiwan in 2000 [[4, 14, 15].]. There was another report of CGD in Malaysia in 2012 [16]. Herein we report 20 cases of CGD from 7 hospitals located both Peninsular and East Malaysia. As with most South East Asian countries, facilities and resources for PID care in Malaysia is limited; mutational analysis was not available locally until the last decade, samples had to be sent overseas.
To the best of our knowledge our report as a CGD patient series is the earliest and the largest from SE Asia; the other large series from Thailand is a PID series of 67 patients which included 6 CGD patients [7]. The mean age of diagnosis for our patients was 3.7 years, much later than Sri Lanka, (1.6 years) and China, (2.24 years) but earlier than India, (4.6 years ) [8, 9, 17].
Chronic granulomatous disease occurs more commonly in males and with X-linked mode of inheritance as seen in two large studies from Europe and USA where males predominate with the former at 81% (351 out of 429) and the latter at 70.5% (259 out of 368 patients), respectively [2, 19]. Similar occurrence was seen in France (88 out of 97 patients, 90.7%) [18]. Predominant mode of autosomal recessive inheritance is seen in reports from India, Iran, Turkey, Israel and Saudi Arabia [9, 21–24]. It is noteworthy that a study done in a province in Saudi Arabia reported that all their patients are autosomal recessive with a point prevalence of 6.4 per 100,000, the highest report up to 2009 in the literature [24]. Positive family history is seen in 40% of the Malaysian series which is higher in large report from China 28% or Italy 35% [17, 25]. We could not conclude that there is a preponderance for autosomal recessive CGD over X-linked CGD in our cohort in view of limited genetic mutational analysis performed. Interestingly 4 of 6 (66%) with p47 Phox, a marker of AR CGD defect were males. Further data on the mutational analysis will be needed to confirm if indeed there is a preponderance of AR CGD over XL CGD in Malaysia
Abscesses are the most common presentation, unlike most other series where pneumonia is the commonest [2, 18, 20, 22]. Pneumonia constitutes only 50% in our series making it the second most common presentation. One of the Malaysian patients had bronchiectasis as a sequela. Bronchiectasis is not a common finding amongst those with lung infections [21]. Brain abscess, a very uncommon presentation, is present in our series. Such presentation has been reported in another series [2, 23]. Lymphadenitis was the most common clinical presentations in some CGD series. However, in the Malaysian cohort it is the third common presentation [8, 19, 21, 24]. Hepatosplenomegaly is also one of the common physical findings (30%).
In term of infectious organism, patients with CGD are prone to catalase-positive bacteria including C violaceum. It is a gram-negative facultative anaerobe which is catalase positive dominating a variety of ecosystem in tropics and sub-tropical regions. It is a rare infection in human with less than 200 cases reported in the literature. [27, 28]. However, they can have a fulminating presentation with a high mortality [29]. Infection in human was first documented in Malaysia (1927) later Singapore, Vietnam, Thailand, Sri Lanka, Taiwan, Hong Kong, India, Australia, Southeast region of USA, and Latin America (Brazil /Argentina) [28, 31]
Earlier report indicated C Violalceum infection in CGD patients as being rare with only one of 368 patients between 1993–1997, US Registry [2]. It is notable Malaysia had 2 reports of C violaceum in CGD patients first in 1994 and a second, later in 2008 [4, 26].
Subsequent literature in the English language (1971–2005) reported more children with invasive C violaceum infection (n = 25) with 36% afflicted with CGD
[30]. However, when considering proportion of CGD patients with C Vioalceum infection, it was 42.9%. and 25% for Thailand and Malaysia respectively [7, 27]. In the present study CGD patients are likely to succumb to C violaceum infection.
Mortality for all C violaceum varies from 53–80%, with higher risk in disseminated form of infection [29]. it is lower for Australia (7.1%) and Southeast USA (11.1%). Mortality of CGD with C violaceum infection is low (7%) in Southeast USA [27, 31] as compared to Malaysia at 80% (present study); interestingly analysis of USA data those 9 grouped as CGD, 6/9 (66.7%) were not diagnosed as CGD at presentation to the hospital [31]
We have within in our present cohort a similar pattern; our 2 patients, P02 & P14, not known to have CGD on admission to the hospital, were found to have CGD subsequently. Patient P02 the younger male sibling of P1 (female) was relatively healthy well until he played football in a muddy field at age of 17 years, ending with a demise with a Chromobacterium violaceum septicemia from an infected wound on the toe. Another Patient 14 who lived in rural Sarawak, East Malaysia close to a swampy area made demise from Chromobacterium violaceum infection with complicating brain abscess after suffering from an infected toe. Both were later revealed the diagnosis as CGD with disseminated form of infection.
The next common infection was Burkholderia pseudomallei ,also waterborne organism presenting as melioidosis. Both of our patients survived with one having undergone HSCT. Other studies reported Staphylococcus spp. as the most common organisms isolated among their CGD patient [18, 19]. However Staphylococcus spp. infection constitutes 10% of our series. Salmonella spp. was noted as the most common pathogen isolated from CGD patients with septicemia [ 2]; however not in our cohort.
Several studies had indicated fungal infections as the predominant organisms in their CGD patients with Aspergillus spp. the predominant fungi isolated [ 9,22,23]. However, Aspergillus spp. was not isolated in our patient samples. Instead Candida spp. and Nocardia were isolated in our laboratory.
Mycobacterium tuberculosis infection afflicted significant proportion of CGD in Sri Lanka, China and South East Asia [8, 17, 23]. Pulmonary tuberculosis is seen in 77% of CGD in Sri Lanka and 31.7% of CGD in Iran [8, 21]. Tuberculosis did not occur as frequently in our series with only 2 (10%) recorded, each of which had lymphadenitis and the other disseminated form of tuberculosis. Complications of BCG are also frequently encountered. A case series from China recorded a high infectious complication from BCG in those with CGD. Of the 45 BCG vaccinated patients, 24 (53%) resulted with BCG infection, mainly in the region confined to the vaccinated site and 2 with disseminated BCG infection / BCGosis [17]. It is notable that patients with CGD tends to develop severe localized BCG infection rather than disseminated BCG infection. In a review by Bustamante et al on mycobacterial infection in CGD, of the 45 with CGD disease, 29 (64.4%) had local or regional BCG disease while 16 (35.6%) others had disseminated BCG disease. [33]
Patients with long standing CGD may develop non-infectious inflammatory complications. Previous studies had indicated various non-infectious inflammatory complications that occurred at different sites of the body. The manifestations included autoimmune manifestations, organ obstruction and granuloma formation. In one study, autoimmune phenomena occurred in about 50% of their CGD patients and, the manifestations included inflammatory bowel disease, reactive arthritis, idiopathic thrombocytopenia and autoimmune hepatitis [22]. Another study showed that granuloma occurred in 68% of their patients and the most common site of this granuloma was in the liver [2]. Wolach et al, described gastric outlet obstruction, urinary outlet obstruction and colitis/enteritis as the most common inflammatory complications [23]. Lupus syndrome was also reported in some of the patients [2]. We recorded one patient with retinitis pigmentosa and discoid lupus. Chorioretinitis had been reported in the case series from Israel [23]. We would suggest for the non-infectious inflammatory complications be actively sought out during the serial clinic follow up.
The serum immunoglobulin level is typically hypergammaglobulinemic in CGD [34, 35] which is ascribed to infections by bacteria and fungi [34, 35]. CD3 + lymphocytosis was seen to a lesser degree with none above 47% in our cohort. However, with low levels, CD4 + lymphopenia was seen 36.4%. Low Immunoglobulin levels are not affected to such degree with ranges between 0–6% only. Interestingly all the 4 (100%) CGD patients with low CD4 lymphopenia had C violaceum infection. Studies of T cell immunity in CGD were reported as normal, but idiopathic CD4 lymphopenia has been a relative common finding. [36]. We cannot hypothesize whether C violaceum is the cause of or the effect of CD4 lymphopenia in the Malaysian CGD series. The answer would come from further studies.
Prevention of infectious complications of CGD includes prophylaxis with appropriate antimicrobial agents; prophylaxis which includes trimethoprim-sulfamethoxazole at 5 mg/kg/day (based on TMP component) and itraconazole at 5 mg/kg/day up to 100 mg daily (if body weight < 50 kg), or 200 mg daily if body weight > 50 kg [37]. Interferon gamma (IFNγ) are not available in Malaysia. The frequency of allogeneic hematopoietic stem cell transplantation (HSCT) as curative treatment options for CGD has increased since 2006 worldwide. The largest retrospective review on the outcome of hematopoietic stem cell transplantation on 712 patients with CGD demonstrated good survival outcome, low incidence of graft failure and mortality in all ages [38]. The allogenic hematopoietic stem cell transplantation in the Malaysian government healthcare service has just recently started for primary immunodeficiency diseases in Malaysia and a patient (P12) from this cohort was successfully underwent HSCT with matched sibling donor [13].
Overall survival of CGD is 90% stretched well to adulthood [26]. Others quoted 81% with long term survival [18]. However, the survival rate is lower in developing countries. The mortality of the patients that we could follow up was 25% which was lower than India (35%) [7], Sri Lanka 38% [6], but higher than the European cohort 20% [14]. [8, 9, 18]. Previous study demonstrated strong association between residual related reactive oxygen intermediates (ROIs) and survival of patients with CGD; where those with little residual production of ROI may fare worse in the severity of illness and survival outcome [39]