**Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases and Clinical Implications**

Attapon Cheepsattayakorn

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/58288

### **1. Introduction**

Human leukocyte antigen (HLA) is the most polymorphic genetic system in humans, with numerous alleles, and subsequently, various possible combinations [1]. These genes, the products of histocompatibility complex (MHC) [2] are located in the short arm of chromo‐ some 6 at band p 21.3 [2] and are divided into three classes, I, II and III [1]. HLA class I is responsible for coding the molecules HLA-A, -B and -C, present in almost all somatic cells with killing of viral infected targets by class I antigens restrict cytotoxic T-cell (CD8+) func‐ tion [2] while HLA class II genes code the molecules HLA-DR, -DQ and -DP [1] by presenta‐ tion of exogenous antigens to T-helper cells (CD4+) or antigen presenting cells (APC) [2]. This polymorphism contributes to the differences in susceptibility to diseases among geneti‐ cally distinct groups [1]. The molecules coded for by the HLA system are responsible for the antigen presentation [1]. The T lymphocytes that are linked to HLA molecules only recog‐ nize antigens by the antigen-specific cell surface receptor-antigens interaction [2], thus the HLA antigens [1] and MCH molecules [2] apparently participate in controlling susceptibility and resistance to various diseases. Some infectious diseases were considered as familial be‐ fore the finding of the causative microorganism and early twin studies indicated that there was a substantial host genetic influence on susceptibility to diseases such as polio and tuber‐ culosis (TB) [3]. At present, it has been confirmed that human genetic variation demon‐ strates a major influence on the course of diseases caused by several infectious microorganisms [3].

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **2. Severe Acute Respiratory Syndrome and HLA**

Recently, Itoyama *et al* reported that the deletion of the 287 bp *Alu* repeat (D allele) in intron 16 of the angiotensin converting enzyme 2 (*ACE 2*) gene is associated with hypoxemia and diffuse alveolar damage in patients with severe acute respiratory syndrome (SARS) [4] and may protect acute lung injury and respiratory failure [5]. Nevertheless, there may be poten‐ tial confounders to a genetic association study as the following: 1) the dead patients were excluded from this study, 2) hypoxemia was defined as requiring oxygen supplementation, and 3) only 44 patients were studied [6]. Some HLA subtypes, particularly *HLA-B\*0703* and *HLA-DRB1\*0301* alleles have been demonstrated to be more prevalent in patients with SARS [7] and those with poorer outcomes [8]. On the other hand, the polymorphism in *ACE II* gene, coding for a functional receptor of the SARS-coronavirus, was not associated with the susceptibility or outcome of SARS [9]. A previous study revealed that *CXCL10(-938AA)* gene is always protective from SARS infection whenever it appears only jointly with either *Fg12(+158T/\*)* or *HO-1 (-497A/\*)*, whereas *Fg12(+158T/\*)* is associated with higher SARS-in‐ fection susceptibility unless combined with *CXCL10/IP-10(-938AA)* which is associated with lower susceptibility [10]. Chan *et al* concluded that the *ACE I/D* polymorphism was not di‐ rectly associated with increasing susceptibility to SARS-coronavirus infection and was not associated with poor outcome after SARS-coronavirus infection [6]. A recent study in Tai‐ wan demonstrated that *HLA*-*Cw\*1502* [11], -*DR\*0301* [11], and -*A\*2402* [12] alleles conferred resistance against SARS infection. CD209L homozygote individuals [13] and low-mannosebinding-lectin-producing genotypes [14] have been demonstrated to have a significantly lower risk and increased risk of SARS infection, respectively. A previous study among Viet‐ namese population with SARS revealed that polymorphisms of two interferon-inducible genes, *2′, 5′-oligoadenylate synthetase 1* (*OAS-1* (G-allele in exon 3 and the one in exon 6)) and *myxovirus resistance-A* (*MxA*) were associated with SARS infection [15]. The single nucleotide polymorphisms (SNPs) in *MxA* was associated with the progression of SARS [15]. The SNPs in *OAS-1* were associated with SARS-coronavirus infection or SARS development [15]. The GG genotype and G-allele of G/T-SNP at position -88 in the *MxA* gene promoter were dem‐ onstrated more frequent in hypoxemic group of patients with SARS than non-hypoxemic group [15]. They may be related to the response of SARS patients to interferons (IFNs), par‐ ticularly those with AA genotype of the A/G-SNP in exon 3 of *OAS-1* may respond to IFN treatment more effectively than those with AG or GG genotype [15]. If SARS re-emerges, IFN could be a promising candidate to treat patients with SARS [16-23]. These findings may contribute to the perception of IFN-induced antiviral response to SARS infection. SARS-co‐ ronavirus infection elicited both CD4+ and CD8+ T-cell responses to the M protein in recov‐ ered SARS patients that persisted for a long period of time [24]. This may have significant implications in developing SARS vaccines [24]. A previous study indicated that a *HLA-A\*0201*-restricted decameric epitope P15 (S411-420, KLPDDFMGCV) derived from the S pro‐ tein that was found to localized within the angiotensin-converting enzyme 2 receptorbinding region of the S1 domain could significantly enhance the expression of *HLA-A\*0201* molecules on the T2 cell surface [25]. P15 then stimulated IFN-γ-producing cytotoxic-T lym‐ phocytes (CTLs) from the peripheral blood mononuclear cells of former SARS patients and induced specific CTLs from P15-immunized *HLA-A\*2.1*-transgenic mice *in vivo* [25]. Signifi‐ cant P15-specific CTLs then were induced by *HLA-A\*2.1*-trangenic mice that was immu‐ nized by a deoxyribonucleic-acid (DNA) vaccine encoding the S protein [25]. This suggested that P15 was a naturally processed epitope [25]. Thus, P15 could be a novel SARS-associated coronavirus-specific epitope and a potential target for evaluation of candidate SARS vac‐

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

325

HLA studies conducted in India revealed that there was association of *HLA-DQ 1* and *-DR 2* antigens with susceptibility of pulmonary TB [26]. A study in North Indian patients demon‐ strated that the allele *DRB 1\*1501* of *HLA-DR 2* was higher compared with *DRB 1\*1502* [26] whereas *HLA-DQB 1\*0601* ( a subtype of *HLA-DQ 1*), *-DRB 1\*1501* and *DPB 1\*02* were demonstrated to be positively associated with pulmonary susceptibility among South Indian patients [26]. Antigen processing gene 2 and mannose-binding protein (MBP) genes along with *HLA-DR2* have been associated with pulmonary TB [26]. Mannose-binding lectin-54 hetero‐ zygotes may be associated with protection against TB meningitis [26]. *HLA-DQB 1\*0601* and *HLA-DRB 1\*0803* were associated with TB disease progression in Korean populations [27]. The frequencies of *HLA-DQB 1\*0402* and antigens DR4 and DR8 were significantly decreased in patients with pulmonary TB but the frequencies of *HLA-DQA1\*0101*, *-DQB1\*0501*, and *- DRB1\*1501* were significantly increased in immunocompetent patients with pulmonary TB [28]. An increased frequency of *HLA-B\*27* in the Greeks, *HLA-A\*2* and *-B\*5* in the Egyptians, *HLA-B\*5*, *-B\*15* and *-DR\*5* in the North American blacks, *HLA-B\*8* in the Canadians was observed [26] whereas *HLA-DQB1\*0502* and -*DQB1\*0503* alleles were demonstrated among the Thai and Vietnamese TB patients, respectively [26, 29]. *HLA-B\*17-tumor-necrosis-factorα-238/A*, *-tumor-necrosis-factor-α-308/2* and *-tumor-necrosis-factor-β-2* have been shown to be associated with TB bacteriological relapse among Indian population [30]. Recently, a novel *HLA-DR*-restricted peptide E7 from the ESAT-6 protein of *Mycobacterium tuberculosis* before and during TB treatment was used to prepare modified *HLA-DR\*08032/E7* and *HLA-DR\*0818/ E7* tetramers to monitor tetramer-positive CD4+ T-cells in direct staining of single specimen and flow cytometric analyses and resulted in 0.1 to 8.8% in the initial pulmonary TB patients' blood, 0.1 to 10.7% in pleural fluid of the initial tuberculous pleuritis patients, 0.02 to 2.2% in non-TB patients' blood, 0.02 to 0.48% in healthy donors' blood and mostly resulted in 0 to 0.2% in umbilical cord blood [31]. After 90-120 days of initial TB symptoms, levels of tetramer-

at 0.03 to 0.3% [31]. Tetramer-positive, interferon-γ-producing and/or tumor-necrosis-factor-

patients could be detected by *in situ* staining [31]. Sensitivity and specificity of tetramer molecules should be confirmed in the future in order to develop possible diagnostic reagents



cines and characterization of virus control mechanisms [25].


**3. Tuberculosis and HLA**

positive CD4+

α-producing CD4<sup>+</sup>

and research [31].

phocytes (CTLs) from the peripheral blood mononuclear cells of former SARS patients and induced specific CTLs from P15-immunized *HLA-A\*2.1*-transgenic mice *in vivo* [25]. Signifi‐ cant P15-specific CTLs then were induced by *HLA-A\*2.1*-trangenic mice that was immu‐ nized by a deoxyribonucleic-acid (DNA) vaccine encoding the S protein [25]. This suggested that P15 was a naturally processed epitope [25]. Thus, P15 could be a novel SARS-associated coronavirus-specific epitope and a potential target for evaluation of candidate SARS vac‐ cines and characterization of virus control mechanisms [25].

### **3. Tuberculosis and HLA**

**2. Severe Acute Respiratory Syndrome and HLA**

324 HLA and Associated Important Diseases

Recently, Itoyama *et al* reported that the deletion of the 287 bp *Alu* repeat (D allele) in intron 16 of the angiotensin converting enzyme 2 (*ACE 2*) gene is associated with hypoxemia and diffuse alveolar damage in patients with severe acute respiratory syndrome (SARS) [4] and may protect acute lung injury and respiratory failure [5]. Nevertheless, there may be poten‐ tial confounders to a genetic association study as the following: 1) the dead patients were excluded from this study, 2) hypoxemia was defined as requiring oxygen supplementation, and 3) only 44 patients were studied [6]. Some HLA subtypes, particularly *HLA-B\*0703* and *HLA-DRB1\*0301* alleles have been demonstrated to be more prevalent in patients with SARS [7] and those with poorer outcomes [8]. On the other hand, the polymorphism in *ACE II* gene, coding for a functional receptor of the SARS-coronavirus, was not associated with the susceptibility or outcome of SARS [9]. A previous study revealed that *CXCL10(-938AA)* gene is always protective from SARS infection whenever it appears only jointly with either *Fg12(+158T/\*)* or *HO-1 (-497A/\*)*, whereas *Fg12(+158T/\*)* is associated with higher SARS-in‐ fection susceptibility unless combined with *CXCL10/IP-10(-938AA)* which is associated with lower susceptibility [10]. Chan *et al* concluded that the *ACE I/D* polymorphism was not di‐ rectly associated with increasing susceptibility to SARS-coronavirus infection and was not associated with poor outcome after SARS-coronavirus infection [6]. A recent study in Tai‐ wan demonstrated that *HLA*-*Cw\*1502* [11], -*DR\*0301* [11], and -*A\*2402* [12] alleles conferred resistance against SARS infection. CD209L homozygote individuals [13] and low-mannosebinding-lectin-producing genotypes [14] have been demonstrated to have a significantly lower risk and increased risk of SARS infection, respectively. A previous study among Viet‐ namese population with SARS revealed that polymorphisms of two interferon-inducible genes, *2′, 5′-oligoadenylate synthetase 1* (*OAS-1* (G-allele in exon 3 and the one in exon 6)) and *myxovirus resistance-A* (*MxA*) were associated with SARS infection [15]. The single nucleotide polymorphisms (SNPs) in *MxA* was associated with the progression of SARS [15]. The SNPs in *OAS-1* were associated with SARS-coronavirus infection or SARS development [15]. The GG genotype and G-allele of G/T-SNP at position -88 in the *MxA* gene promoter were dem‐ onstrated more frequent in hypoxemic group of patients with SARS than non-hypoxemic group [15]. They may be related to the response of SARS patients to interferons (IFNs), par‐ ticularly those with AA genotype of the A/G-SNP in exon 3 of *OAS-1* may respond to IFN treatment more effectively than those with AG or GG genotype [15]. If SARS re-emerges, IFN could be a promising candidate to treat patients with SARS [16-23]. These findings may contribute to the perception of IFN-induced antiviral response to SARS infection. SARS-co‐ ronavirus infection elicited both CD4+ and CD8+ T-cell responses to the M protein in recov‐ ered SARS patients that persisted for a long period of time [24]. This may have significant implications in developing SARS vaccines [24]. A previous study indicated that a *HLA-A\*0201*-restricted decameric epitope P15 (S411-420, KLPDDFMGCV) derived from the S pro‐ tein that was found to localized within the angiotensin-converting enzyme 2 receptorbinding region of the S1 domain could significantly enhance the expression of *HLA-A\*0201* molecules on the T2 cell surface [25]. P15 then stimulated IFN-γ-producing cytotoxic-T lym‐

HLA studies conducted in India revealed that there was association of *HLA-DQ 1* and *-DR 2* antigens with susceptibility of pulmonary TB [26]. A study in North Indian patients demon‐ strated that the allele *DRB 1\*1501* of *HLA-DR 2* was higher compared with *DRB 1\*1502* [26] whereas *HLA-DQB 1\*0601* ( a subtype of *HLA-DQ 1*), *-DRB 1\*1501* and *DPB 1\*02* were demonstrated to be positively associated with pulmonary susceptibility among South Indian patients [26]. Antigen processing gene 2 and mannose-binding protein (MBP) genes along with *HLA-DR2* have been associated with pulmonary TB [26]. Mannose-binding lectin-54 hetero‐ zygotes may be associated with protection against TB meningitis [26]. *HLA-DQB 1\*0601* and *HLA-DRB 1\*0803* were associated with TB disease progression in Korean populations [27]. The frequencies of *HLA-DQB 1\*0402* and antigens DR4 and DR8 were significantly decreased in patients with pulmonary TB but the frequencies of *HLA-DQA1\*0101*, *-DQB1\*0501*, and *- DRB1\*1501* were significantly increased in immunocompetent patients with pulmonary TB [28]. An increased frequency of *HLA-B\*27* in the Greeks, *HLA-A\*2* and *-B\*5* in the Egyptians, *HLA-B\*5*, *-B\*15* and *-DR\*5* in the North American blacks, *HLA-B\*8* in the Canadians was observed [26] whereas *HLA-DQB1\*0502* and -*DQB1\*0503* alleles were demonstrated among the Thai and Vietnamese TB patients, respectively [26, 29]. *HLA-B\*17-tumor-necrosis-factorα-238/A*, *-tumor-necrosis-factor-α-308/2* and *-tumor-necrosis-factor-β-2* have been shown to be associated with TB bacteriological relapse among Indian population [30]. Recently, a novel *HLA-DR*-restricted peptide E7 from the ESAT-6 protein of *Mycobacterium tuberculosis* before and during TB treatment was used to prepare modified *HLA-DR\*08032/E7* and *HLA-DR\*0818/ E7* tetramers to monitor tetramer-positive CD4+ T-cells in direct staining of single specimen and flow cytometric analyses and resulted in 0.1 to 8.8% in the initial pulmonary TB patients' blood, 0.1 to 10.7% in pleural fluid of the initial tuberculous pleuritis patients, 0.02 to 2.2% in non-TB patients' blood, 0.02 to 0.48% in healthy donors' blood and mostly resulted in 0 to 0.2% in umbilical cord blood [31]. After 90-120 days of initial TB symptoms, levels of tetramerpositive CD4+ -T cells in tetramer-positive CD4+ -T cells reached and kept at low even normal at 0.03 to 0.3% [31]. Tetramer-positive, interferon-γ-producing and/or tumor-necrosis-factorα-producing CD4<sup>+</sup> -T cells in pulmonary granuloma, lymph node and cavernous tissues of TB patients could be detected by *in situ* staining [31]. Sensitivity and specificity of tetramer molecules should be confirmed in the future in order to develop possible diagnostic reagents and research [31].

### **4. Human Immunodeficiency Virus Infection (HIV)/Acquired Immunodeficiency Syndrome (AIDS) — Related tropical pulmonary infectious diseases and HLA**

**4.2. HIV-infection/AIDS-related community acquired pneumonia**

and the United States of America [40].

**infection**

A previous study in Kenya in 1976 demonstrated that 20% of patients presenting with pneumonia to Kenyatta National Hospital had pneumococcal bacteremia which was very common among HIV-infected patients (26% of the HIV-1 seropositive group versus 6% of the seronegative group) [40] whereas *Streptococcus pneumoniae* pneumonia has been the most common cause of bacterial pneumonia same as in the pre-AIDS era [32]. Approximately, 17% of medically hospital admissions to the one of East Africa's largest hospital are community acquired pneumonia (CAP) [32]. Gilks *et al* reported that invasive pneumococcal disease among the female prostitutes in Nairobi, Kenya was the most frequently encountered serious HIV-associated infection and was more common than TB [40]. Pneumococcal pneumonia occurred at a significantly higher rate among HIV- seropositive patients, particularly HIV-1 serotype [40]. The clinical presentation of pyogenic pneumonia in HIV-1 seropositive patients was similar to that observed in HIV-seronegative ones [40]. The acute onset of fever and cough was the most common presentation [40]. Although, approximately, 10% of patients with lobar pneumonia in the tropics fail to improve with penicillin treatment, there is no significant difference in penicillin treatment response in both HIV-seropositive and HIV-seronegative patients [40]. In tropical and developing countries, penicillin, because of it antimicrobial tolerance and cheapness, is still the drug of choice for CAP regardless of HIV status [40]. The mortality rate was higher among HIV-1 seropositive patients with CAP than HIV-1 seroneg‐ ative persons with CAP (17% versus 8%) [40]. Recurrence of pneumococcal disease occurred 22% among the prostitutes in Nairobi, Kenya which rate of recurrence increased both in Kenya

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

327

**4.3. HIV-infection/AIDS-related pulmonary** *Nocardia asteroides* **infectionasteroides**

*Nocardiaasteroides* is a branching filamentous, beaded Gram-positive-rod microorganism which is usually found worldwide in soil and decaying organic matter and usually produces disease in immunocompromised persons, particularly HIV-1 infected individuals although few cases have been reported from the tropical regions [32]. The earliest report of AIDS patients from Rwanda demonstrated one of 26 cases diagnosing *Nocardia asteroides* pleuropneumonia whereas one of 50 AIDS patients with pulmonary interstitial infiltrates in Zimbabwe was diagnosed pneumonia [32]. In previous studies in Uganda, Cote d' Ivoire, and Zaire, three of the 57, one of 52, and occasional AIDS patients who underwent post-mortem examination revealed histopathologically pulmonary military nocardiosis, respectively [32]. Clinical manifestations of pulmonary nocardiosis in HIV-1 infected patients are usually non-specific [32]. The majority of cases present with fever, cough, night sweats, malaise, and body weight loss [32]. Although nocardiosis is frequently disseminated at the presentation, the lungs are the most common site of involvement, particularly upper lobes [32]. Thus, pulmonary nocardiosis is roentgenographically indistinguishable from pulmonary TB [32]. Because of rarely positive-blood culture, culture of the respiratory specimens is the definitely diagnostic method [32]. Due to 47% of patients was indicated of nocardiosis so the diagnosis should be suspected if the characteristic morphology is detected on Gram staining [41]. This microor‐

The World Health Organization (WHO) estimates that 8-10 million new cases of TB globally occur each year [32]. Although AIDS is the same disease as HIV disease in all part of the world, this microorganism is mostly in many tropical countries [32]. In tropical countries, TB and bacterial pneumonia represent the major pulmonary infections among the patients with HIVinfection/AIDS [32]. Although the spectrum of HIV disease/AIDS is quite broad, the majority of the pulmonary infections in HIV-1 infected patients are similar to those observed in non-HIV infected persons [32]. The geographical differences are primarily due to varying frequen‐ cies rather than the kinds of infections [32]. Of all the pulmonary infections encountered in the tropics obviously *Mycobacterium tuberculosis* is one of the most significant pathogenic micro‐ organisms [32]. A recent study on HLA and AIDS in children with AIDS revealed that the presence of homozygous *HLA-B* or *-C* alleles was associated with more rapid disease progres‐ sion, in contrast, the presence of *HLA-B\*27* or *-B\*57* alleles was associated with slower disease progression which remained significant after adjustment for age, gender, race, and baseline HIV-1 log ribonucleic acid (RNA), CD4+ -T cell count and percent and weight for age Z score or other genetic variants including *CCR5-wt/Δ32* (CCR5 = chemokine (C-C motif) receptor 5), *-59029-G/A*, *CCR2-wt/64I* (CCR2 = chemokine (C-C motif) receptor 2), *CX3CR1-249-V/I*(CX3CR1 = chemokine (C-C motif) ligand 3-like 1), *-280-T/M*, *SDF-1-180-G/A* (SDF-1 = stromal cellderived factor-1), *MCP-1-G/A* (MCP-1 = monocyte chemotactic protein-1), *MBL2-A/O* (MBL = mannose-binding lectin), *MBL2-X/Y* (MBL = mannose-binding lectin), *MBL2-P/Q* (MBL = mannose-binding lectin), and *MBL2-H/L* (MBL = mannose-binding lectin) [33]. Additionally, the *HLA-A\*24* allele was associated with more rapid central nervous system (CNS) impairment and the *HLA-Cw2* allele protected against disease progression [33]. For HLA class II, the presence of the *HLA-DQB1\*2* allele protected against both HIV-1 disease progression and CNS impairment [33]. HLA concordance between a mother and her infant is associated with increased risk of HIV transmission whereas HLA discordance decreases the risk of mother-tochild HIV transmission [34, 35]. HLA class I homozygosity [36, 37] and children who have the same HLA class I alleles at both sites with their mothers at one of more HLA locus [38] are at increased risk for more rapid disease progression.

#### **4.1. HIV-infection/AIDS-TB Co-infection and HLA**

Studies from Haiti and sub-Saharan Africa have demonstrated that 17% to 66% of TB cases are HIV-1 seropositive while 50% of HIV-seropositive patients with pulmonary symptoms are sick with TB [32]. A previous study in Brazilians by Figueiredo *et al*revealed that *HLA-A\*31*, *HLA-B\*41*, *HLA-DQB1\*5*, and *HLA-DRB1\*10* alleles, were over- represented in acquired-immuno‐ deficiency-syndrome (AIDS) patients with TB, indicated that these HLA molecules are associated with susceptibility to TB in Brazilian patients with AIDS [39].

### **4.2. HIV-infection/AIDS-related community acquired pneumonia**

**4. Human Immunodeficiency Virus Infection (HIV)/Acquired**

**infectious diseases and HLA**

326 HLA and Associated Important Diseases

HIV-1 log ribonucleic acid (RNA), CD4+

increased risk for more rapid disease progression.

**4.1. HIV-infection/AIDS-TB Co-infection and HLA**

**Immunodeficiency Syndrome (AIDS) — Related tropical pulmonary**

The World Health Organization (WHO) estimates that 8-10 million new cases of TB globally occur each year [32]. Although AIDS is the same disease as HIV disease in all part of the world, this microorganism is mostly in many tropical countries [32]. In tropical countries, TB and bacterial pneumonia represent the major pulmonary infections among the patients with HIVinfection/AIDS [32]. Although the spectrum of HIV disease/AIDS is quite broad, the majority of the pulmonary infections in HIV-1 infected patients are similar to those observed in non-HIV infected persons [32]. The geographical differences are primarily due to varying frequen‐ cies rather than the kinds of infections [32]. Of all the pulmonary infections encountered in the tropics obviously *Mycobacterium tuberculosis* is one of the most significant pathogenic micro‐ organisms [32]. A recent study on HLA and AIDS in children with AIDS revealed that the presence of homozygous *HLA-B* or *-C* alleles was associated with more rapid disease progres‐ sion, in contrast, the presence of *HLA-B\*27* or *-B\*57* alleles was associated with slower disease progression which remained significant after adjustment for age, gender, race, and baseline

or other genetic variants including *CCR5-wt/Δ32* (CCR5 = chemokine (C-C motif) receptor 5), *-59029-G/A*, *CCR2-wt/64I* (CCR2 = chemokine (C-C motif) receptor 2), *CX3CR1-249-V/I*(CX3CR1 = chemokine (C-C motif) ligand 3-like 1), *-280-T/M*, *SDF-1-180-G/A* (SDF-1 = stromal cellderived factor-1), *MCP-1-G/A* (MCP-1 = monocyte chemotactic protein-1), *MBL2-A/O* (MBL = mannose-binding lectin), *MBL2-X/Y* (MBL = mannose-binding lectin), *MBL2-P/Q* (MBL = mannose-binding lectin), and *MBL2-H/L* (MBL = mannose-binding lectin) [33]. Additionally, the *HLA-A\*24* allele was associated with more rapid central nervous system (CNS) impairment and the *HLA-Cw2* allele protected against disease progression [33]. For HLA class II, the presence of the *HLA-DQB1\*2* allele protected against both HIV-1 disease progression and CNS impairment [33]. HLA concordance between a mother and her infant is associated with increased risk of HIV transmission whereas HLA discordance decreases the risk of mother-tochild HIV transmission [34, 35]. HLA class I homozygosity [36, 37] and children who have the same HLA class I alleles at both sites with their mothers at one of more HLA locus [38] are at

Studies from Haiti and sub-Saharan Africa have demonstrated that 17% to 66% of TB cases are HIV-1 seropositive while 50% of HIV-seropositive patients with pulmonary symptoms are sick with TB [32]. A previous study in Brazilians by Figueiredo *et al*revealed that *HLA-A\*31*, *HLA-B\*41*, *HLA-DQB1\*5*, and *HLA-DRB1\*10* alleles, were over- represented in acquired-immuno‐ deficiency-syndrome (AIDS) patients with TB, indicated that these HLA molecules are

associated with susceptibility to TB in Brazilian patients with AIDS [39].


A previous study in Kenya in 1976 demonstrated that 20% of patients presenting with pneumonia to Kenyatta National Hospital had pneumococcal bacteremia which was very common among HIV-infected patients (26% of the HIV-1 seropositive group versus 6% of the seronegative group) [40] whereas *Streptococcus pneumoniae* pneumonia has been the most common cause of bacterial pneumonia same as in the pre-AIDS era [32]. Approximately, 17% of medically hospital admissions to the one of East Africa's largest hospital are community acquired pneumonia (CAP) [32]. Gilks *et al* reported that invasive pneumococcal disease among the female prostitutes in Nairobi, Kenya was the most frequently encountered serious HIV-associated infection and was more common than TB [40]. Pneumococcal pneumonia occurred at a significantly higher rate among HIV- seropositive patients, particularly HIV-1 serotype [40]. The clinical presentation of pyogenic pneumonia in HIV-1 seropositive patients was similar to that observed in HIV-seronegative ones [40]. The acute onset of fever and cough was the most common presentation [40]. Although, approximately, 10% of patients with lobar pneumonia in the tropics fail to improve with penicillin treatment, there is no significant difference in penicillin treatment response in both HIV-seropositive and HIV-seronegative patients [40]. In tropical and developing countries, penicillin, because of it antimicrobial tolerance and cheapness, is still the drug of choice for CAP regardless of HIV status [40]. The mortality rate was higher among HIV-1 seropositive patients with CAP than HIV-1 seroneg‐ ative persons with CAP (17% versus 8%) [40]. Recurrence of pneumococcal disease occurred 22% among the prostitutes in Nairobi, Kenya which rate of recurrence increased both in Kenya and the United States of America [40].

#### **4.3. HIV-infection/AIDS-related pulmonary** *Nocardia asteroides* **infectionasteroides infection**

*Nocardiaasteroides* is a branching filamentous, beaded Gram-positive-rod microorganism which is usually found worldwide in soil and decaying organic matter and usually produces disease in immunocompromised persons, particularly HIV-1 infected individuals although few cases have been reported from the tropical regions [32]. The earliest report of AIDS patients from Rwanda demonstrated one of 26 cases diagnosing *Nocardia asteroides* pleuropneumonia whereas one of 50 AIDS patients with pulmonary interstitial infiltrates in Zimbabwe was diagnosed pneumonia [32]. In previous studies in Uganda, Cote d' Ivoire, and Zaire, three of the 57, one of 52, and occasional AIDS patients who underwent post-mortem examination revealed histopathologically pulmonary military nocardiosis, respectively [32]. Clinical manifestations of pulmonary nocardiosis in HIV-1 infected patients are usually non-specific [32]. The majority of cases present with fever, cough, night sweats, malaise, and body weight loss [32]. Although nocardiosis is frequently disseminated at the presentation, the lungs are the most common site of involvement, particularly upper lobes [32]. Thus, pulmonary nocardiosis is roentgenographically indistinguishable from pulmonary TB [32]. Because of rarely positive-blood culture, culture of the respiratory specimens is the definitely diagnostic method [32]. Due to 47% of patients was indicated of nocardiosis so the diagnosis should be suspected if the characteristic morphology is detected on Gram staining [41]. This microor‐ ganism is also weakly stains the acid fast [32]. According to ability to stain the acid fast coupled with the roentgenographic presentation of this microbial pulmonary infection, it may contrib‐ ute to be misdiagnosed as pulmonary TB [32]. It is likely that sulphonamides (trimethoprimsulphamethoxazole) will be effective in HIV-1 infected patients with nocardiosis whereas sulphonamides have been the treatment of choice for nocardiosis in non-HIV-1 infected patients [32]. Other antimicrobial agents with *in vitro* bactericidal activity to *Nocardia ÿste‐ roids* include amoxicillin-clavulanic acid, minocycline, amikacin, and third-generation cephalosporin [32]. Treatment duration is at least 6 to 12 months and, perhaps, indefinitely since recurrences have been reported [32].

**4.5. HIV-infection/AIDS-related fungal pneumonia**

*Histoplasma capsulatum* is a dimorphic soil dwelling fungus which is rare in Africa before the AIDS epidemic [43]. This microorganism is endemic in the Americas [43]. Histoplasmosis was reported in 1984 in a Zairean AIDS patients and subsequently was identified in a few post-mortem-examined lungs in Zaire [43]. African histoplasmosis is also caused by *Histo‐ plasma duboisii*, a fungal disease which is not increased in Congo but occurs mainly in Cen‐ tral and West Africa [44]. Carme *et al* reported a 26-year-old Congolese male with disseminated *Histoplasma duboisii* infection [45]. In 1987, a white heterosexual European pa‐ tient was reported with African histoplasmosis [46, 47]. Three Belgian AIDS patients who had lived in Africa disseminated *Histoplasma duboisii* infection whereas one of these patients developed pulmonary disease [48]. An African HIV-2 infected child from Guinea Bissau was reported with disseminated disease [46]. Amphotericin B remains the drug of choice for the treatment of histoplasmosis with AIDS [49]. Ketoconazole, with or without a prior course of amphotericin B, has been used, but sometimes with unacceptable results [50]. After induc‐ tion therapy, patients should be maintained on lifelong maintenance therapy with either

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

329

weekly intravenous amphotericin B, oral itraconazole, or oral fluconazole [50].

*Cryptococcus neoformans*, a budding encapsulated yeast is distributed worldwide [50]. In Hai‐ ti, the prevalence of cryptococcosis among AIDS patients was approximately 13% whereas as many as 30% of AIDS patients in some areas of subsahara Africa had cryptococcosis [51]. Most of the patients present with disseminated disease or meningitis although the lungs is the usual portal of entry, thus, isolated pulmonary involvement is unusual [32]. A previous study in Bujumbura, Burundi demonstrated that only one patients of 222 cases was diag‐ nosed cryptococcal pneumonia [52] while two of 40 Ugandan patients in a previous study were diagnosed cryptococcal pneumonia [53] but no cases with pulmonary cryptococcosis in Cote d' Ivoire was reported in a post-mortem study [54]. Previous data from Rwanda in‐ dicated that cryptococcal pneumonia was common in this country [55, 56]. Between January 1990 and March 1992, 28 Rwandese HIV-1 infected patients were diagnosed cryptococcal pneumonia by isolation from sputum, pleural fluid, and bronchoalveolar lavage (BAL) [55]. The serum cryptococcal antigen testing was negative in all patients without extrapulmonary site of infection [55]. Generally, there are two varieties of *Cryptococcus neoformans,* and gattii [57]. Most HIV-1 infected cases were reported of neoformans variety [57]. Variety gattii is mainly restricted to tropical and subtropical areas [57]. Since 1987, six cases of variety gattii have been reported from Rwanda, Brazil, and Zaire [57]. One Rwandese patient with nega‐ tive serum and cerebrospinal fluid cryptococcal antigen demonstrated right hilar adenop‐ athy accompanying a right lower lung infiltrate [57]. *Cryptococcus neoformans* variety gattii was isolated from the BAL fluid when the patient did not respond to penicillin and trime‐ thoprim-sulphamethoxazole [57]. Taelman *et al* demonstrated that itraconazole( 200 mg/

*4.5.1. Pulmonary histoplasmosis*

*4.5.2. Pulmonary cryptococcosis*

#### **4.4. HIV-infection/AIDS-related pulmonary melioidosis**

Melioidosis is caused by the Gram-negative motile bacillus, *Burkholderia (Pseudomonas) pseudomallei* [32]. A previous study in Bangkok, Thailand, 49 cases were observed between 1975 and 1987 [32]. Of these patients, 20 had localized disease while 29 had disseminated disease [32]. Almost all of these patients had an underlying immunocompromised condition like hematological malignancy, collagen vascular disease, and diabetes mellitus [32]. One case had AIDS and presented with left lung infiltrates and recurrent bacteremic melioidosis [32]. More than 750 cases of melioidosis have occurred during the last two decades, and over 75% of the patients were farmers [32]. The disease is endemic in southeast Asia, west Africa, and northern Australia [32]. The clinical manifestations of melioidosis are non- specific but in immunocompromised patients, they usually present with fever and pulmonary infiltrates [32]. The roentgenographic presentation is also non-specific and may demonstrate diffuse infil‐ trates, hilar adenopathy, lung abscess, or extensive pneumonia, thus the diagnosis requires isolation of this microorganism, particularly by culture of blood and/or respiratory samples in cases with disseminated disease [32]. A previous study by Cheepsattayakorn *et al* at the 10th Zonal Tuberculosis and Chest Disease Center, Chiang Mai, Thailand in 2001 among a number of patients with clinical and roentgenographic presentations mimicked *Burkholderia (Pseudo‐ monas) pseudomallei* pneumonia revealed no detection of the laboratory-confirmed cases but having dramatic response to 6-12 months of tetracycline treatment [42]. A previous study in Thailand reported that 14 immunocompromised melioidosis patients with disease dissemi‐ nation had a treatment delay or were appropriately treated, all but one were dead [32]. Thus, rapid and early diagnosis and treatment with combined antimicrobials is crucial [32]. It should be emphasized that most HIV- infected/AIDS patients in Thailand are urban dwellers and that most melioidosis cases occur in farmers [32]. Thus, the incidence of melioidosis is expected to increase as the HIV epidemic spread into rural area [32]. *Burkholderia (Pseudomonas) pseudo‐ mallei* is usually susceptible to tetracycline, chloramphenicol, trimethoprim-sulphamethoxa‐ zole, and third-generation cephalosporin [32]. If the patient is seriously clinical toxic, two antimicrobials are usually recommended during the initial 30 days and followed by 60-150 days of trimethoprim-sulphamethoxazole alone [32]. In septicemic melioidosis, trimethoprimsulphamethoxazole plus a third-generation cephalosporin are recommended [32]. For patients who are intolerant to trimethoprim-sulphamethoxazole, another antimicrobial listed above should be replaced [32].

#### **4.5. HIV-infection/AIDS-related fungal pneumonia**

#### *4.5.1. Pulmonary histoplasmosis*

ganism is also weakly stains the acid fast [32]. According to ability to stain the acid fast coupled with the roentgenographic presentation of this microbial pulmonary infection, it may contrib‐ ute to be misdiagnosed as pulmonary TB [32]. It is likely that sulphonamides (trimethoprimsulphamethoxazole) will be effective in HIV-1 infected patients with nocardiosis whereas sulphonamides have been the treatment of choice for nocardiosis in non-HIV-1 infected patients [32]. Other antimicrobial agents with *in vitro* bactericidal activity to *Nocardia ÿste‐ roids* include amoxicillin-clavulanic acid, minocycline, amikacin, and third-generation cephalosporin [32]. Treatment duration is at least 6 to 12 months and, perhaps, indefinitely

Melioidosis is caused by the Gram-negative motile bacillus, *Burkholderia (Pseudomonas) pseudomallei* [32]. A previous study in Bangkok, Thailand, 49 cases were observed between 1975 and 1987 [32]. Of these patients, 20 had localized disease while 29 had disseminated disease [32]. Almost all of these patients had an underlying immunocompromised condition like hematological malignancy, collagen vascular disease, and diabetes mellitus [32]. One case had AIDS and presented with left lung infiltrates and recurrent bacteremic melioidosis [32]. More than 750 cases of melioidosis have occurred during the last two decades, and over 75% of the patients were farmers [32]. The disease is endemic in southeast Asia, west Africa, and northern Australia [32]. The clinical manifestations of melioidosis are non- specific but in immunocompromised patients, they usually present with fever and pulmonary infiltrates [32]. The roentgenographic presentation is also non-specific and may demonstrate diffuse infil‐ trates, hilar adenopathy, lung abscess, or extensive pneumonia, thus the diagnosis requires isolation of this microorganism, particularly by culture of blood and/or respiratory samples in cases with disseminated disease [32]. A previous study by Cheepsattayakorn *et al* at the 10th Zonal Tuberculosis and Chest Disease Center, Chiang Mai, Thailand in 2001 among a number of patients with clinical and roentgenographic presentations mimicked *Burkholderia (Pseudo‐ monas) pseudomallei* pneumonia revealed no detection of the laboratory-confirmed cases but having dramatic response to 6-12 months of tetracycline treatment [42]. A previous study in Thailand reported that 14 immunocompromised melioidosis patients with disease dissemi‐ nation had a treatment delay or were appropriately treated, all but one were dead [32]. Thus, rapid and early diagnosis and treatment with combined antimicrobials is crucial [32]. It should be emphasized that most HIV- infected/AIDS patients in Thailand are urban dwellers and that most melioidosis cases occur in farmers [32]. Thus, the incidence of melioidosis is expected to increase as the HIV epidemic spread into rural area [32]. *Burkholderia (Pseudomonas) pseudo‐ mallei* is usually susceptible to tetracycline, chloramphenicol, trimethoprim-sulphamethoxa‐ zole, and third-generation cephalosporin [32]. If the patient is seriously clinical toxic, two antimicrobials are usually recommended during the initial 30 days and followed by 60-150 days of trimethoprim-sulphamethoxazole alone [32]. In septicemic melioidosis, trimethoprimsulphamethoxazole plus a third-generation cephalosporin are recommended [32]. For patients who are intolerant to trimethoprim-sulphamethoxazole, another antimicrobial listed above

since recurrences have been reported [32].

328 HLA and Associated Important Diseases

should be replaced [32].

**4.4. HIV-infection/AIDS-related pulmonary melioidosis**

*Histoplasma capsulatum* is a dimorphic soil dwelling fungus which is rare in Africa before the AIDS epidemic [43]. This microorganism is endemic in the Americas [43]. Histoplasmosis was reported in 1984 in a Zairean AIDS patients and subsequently was identified in a few post-mortem-examined lungs in Zaire [43]. African histoplasmosis is also caused by *Histo‐ plasma duboisii*, a fungal disease which is not increased in Congo but occurs mainly in Cen‐ tral and West Africa [44]. Carme *et al* reported a 26-year-old Congolese male with disseminated *Histoplasma duboisii* infection [45]. In 1987, a white heterosexual European pa‐ tient was reported with African histoplasmosis [46, 47]. Three Belgian AIDS patients who had lived in Africa disseminated *Histoplasma duboisii* infection whereas one of these patients developed pulmonary disease [48]. An African HIV-2 infected child from Guinea Bissau was reported with disseminated disease [46]. Amphotericin B remains the drug of choice for the treatment of histoplasmosis with AIDS [49]. Ketoconazole, with or without a prior course of amphotericin B, has been used, but sometimes with unacceptable results [50]. After induc‐ tion therapy, patients should be maintained on lifelong maintenance therapy with either weekly intravenous amphotericin B, oral itraconazole, or oral fluconazole [50].

#### *4.5.2. Pulmonary cryptococcosis*

*Cryptococcus neoformans*, a budding encapsulated yeast is distributed worldwide [50]. In Hai‐ ti, the prevalence of cryptococcosis among AIDS patients was approximately 13% whereas as many as 30% of AIDS patients in some areas of subsahara Africa had cryptococcosis [51]. Most of the patients present with disseminated disease or meningitis although the lungs is the usual portal of entry, thus, isolated pulmonary involvement is unusual [32]. A previous study in Bujumbura, Burundi demonstrated that only one patients of 222 cases was diag‐ nosed cryptococcal pneumonia [52] while two of 40 Ugandan patients in a previous study were diagnosed cryptococcal pneumonia [53] but no cases with pulmonary cryptococcosis in Cote d' Ivoire was reported in a post-mortem study [54]. Previous data from Rwanda in‐ dicated that cryptococcal pneumonia was common in this country [55, 56]. Between January 1990 and March 1992, 28 Rwandese HIV-1 infected patients were diagnosed cryptococcal pneumonia by isolation from sputum, pleural fluid, and bronchoalveolar lavage (BAL) [55]. The serum cryptococcal antigen testing was negative in all patients without extrapulmonary site of infection [55]. Generally, there are two varieties of *Cryptococcus neoformans,* and gattii [57]. Most HIV-1 infected cases were reported of neoformans variety [57]. Variety gattii is mainly restricted to tropical and subtropical areas [57]. Since 1987, six cases of variety gattii have been reported from Rwanda, Brazil, and Zaire [57]. One Rwandese patient with nega‐ tive serum and cerebrospinal fluid cryptococcal antigen demonstrated right hilar adenop‐ athy accompanying a right lower lung infiltrate [57]. *Cryptococcus neoformans* variety gattii was isolated from the BAL fluid when the patient did not respond to penicillin and trime‐ thoprim-sulphamethoxazole [57]. Taelman *et al* demonstrated that itraconazole( 200 mg/ day) was effective in preventing future disease dissemination for Rwandese patients with isolated pulmonary cryptococcosis [56]. Fluconazole (400-800 mg/day) has been shown to be effective as primary treatment as well as long-term therapy (200- 400 mg/day) [50]. In the USA, the drug of choice for treatment of cryptococcosis is amphotericin B, with or without flucytosine [50]. Nevertheless, these antimicrobials are frequently not available in tropical countries [50].

disease/AIDS, 75% of the patients may develop *Pneumocystis jeroveci (carinii)* pneumonia (PCP) [64]. A previous study by Cheepsattayakorn *et al* at the 10th Zonal Tuberculosis and Chest Disease center, Chiang Mai, Thailand between 1999 and 2000 among 49 HIV-infected/ AIDS patients who had clinical manifestations and chest roentgenographic findings compat‐ ible with PCP revealed that only one patient demonstrated induced sputum-reverse tran‐ scriptase polymerase chain reaction (RT-PCR)- confirmed PCP whereas two patients were confirmed by blood RT-PCR [65]. Nevertheless, the frequency of PCP is quite different in tropical countries [66]. Blaser *et al* reported that 20% of PCP occurred among HIV-infected/ AIDS individuals native to the tropics (35%) was significantly lower than for HIV-infected/ AIDS individuals in more developed countries (73%) [66]. PCP has been detected in 37% of AIDS patients of African origin in the USA and in 14-24% of African patients with AIDS treated in Europe [67]. The question is whether the exposure to *Pneumocystis jeroveci (carinii)* occurred in Africa or after leaving is not known. A previous study from Zimbabwe reported that of 50 HIV-infected/AIDS patients with acute interstitial pneumonia, 17 and 16 were di‐ agnosed PCP and TB, respectively [68]. By using sputum induction with hypertonic saline, researchers in Tanzania reported that 3 of 83 specimens (3-6%) were positive for *Pneumocys‐ tis jeroveci (carinii)* [69]. A number of previous studies in 229 AIDS cases from Haiti indicated that PCP was detected in only 7% of 131 cases compared with 71% of the first 80 AIDS pa‐ tients noted at the New York Hospital in New York City, USA [70]. Chequer *et al* reported their study in Brazil of 2,135 adult AIDS patients and demonstrated that 425 cases (20%) were diagnosed PCP whereas PCP plus another infection was detected in 265 cases (12%) [71] whereas 45% of homosexual urban AIDS patients in southern Brazil were diagnosed PCP [72]. The clinical and roentgenographic presentations of PCP are likely to be similar among the different regions [68]. Nevertheless, the frequent occurrence of TB in developing countries makes differentiation of the two diseases difficult [68], but in one study, the clini‐ cal picture most consistent with PCP was a respiratory rate of over 40/minute [68]. In con‐ trast, the coarse reticulonodular infiltrates on the chest roentgenogram is most likely to be TB [68]. Currently, the treatment of choice for PCP is trimethoprim-sulphamethoxazole [32]. Other alternative antipneumocystis drugs are often not available in the tropical countries [32]. It has been postulated that HIV-infected/AIDS patients in the tropics die before they be‐

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

331

come immunocompromised enough to develop PCP [54, 73, 74].

Very few parasitic diseases have been reported to cause pneumonia in HIV- infected/AIDS patients [32]. A helminth, *Strongyloides stercoralis* which is commonly found in many tropical and subtropical areas, has occasionally been reported as the cause of pulmonary disease [32]. The prevalence of this helminth in stool specimen varies from region to region as the following : 26-48% in subsahara Africa, 15-82% in Brazil, 1-16% in Ecuador, and 4-40% in the USA [75]. Although the prevalence of strongyloides infection in southeast Asia is high, but no cases have been reported in the English language literature [32]. There have been rela‐

**4.6. HIV-infection/AIDS-related parasitic pneumonia**

*4.6.1. Pulmonary strongyloidiasis*

#### *4.5.3. Pulmonary paracoccidioidomycosis*

Paracoccidioidomycosis is caused by the dimorphic fungus *Paracoccidioides brasiliensis* [58]*.* The patients with paracoccidioidomycosis may present with cutaneous form, isolated pul‐ monary involvement, or disseminated form [58]. Most patients present with disseminated involvement [58]. Only few cases involving HIV-1 infection have been reported despite its endemicity [58]. The chest roentgenographic findings demonstrate notable diffuse reticulo‐ nodular infiltrates, and sometimes with hilar adenopathy [59]. Patients have been success‐ fully treated with various regimens including amphotericin B, imidazole compounds, and sulphadiazine [60]. Itraconazole (100 mg/day) appears to be more effective than ketocona‐ zole (200-400 mg/day) which has been successfully used to treat paracoccidioidomycosis in immunocompetent patients with unknown treatment duration [60]. Nevertheless, the rec‐ ommended treatment duration is 6 to 18 months [60]. At least two patients have been placed on suppressive therapy with sulphadiazine (1-6 g/day) for lifelong prophylaxis with good early results [60].

#### *4.5.4. Pulmonary penicillosis*

This disease caused by the usual dimorphic fungus, *Penicillium marneffei*, both in normal and immunocompromised hosts [61]. This fungus is endemic to southeast Asia and southern China [61]. Most cases have been reported as a systemic mycoses [61]. A previous study from Thailand demonstrated that 11 of the 21 patients had a cough as their presentation [61]. Of the 6 cases with abnormal chest roentgenographic findings, 3 showed diffuse reticulo‐ nodular infiltrates, 2 had localized interstitial infiltrates, and 1 had a focal alveolar infiltrate [61]. Definite diagnosis is usually made from cultures of blood, bone marrow, or skin biopsy [61]. The current treatment of choice is 6-8 weeks of Amphotericin B (40 mg/kg) [32]. In in above study in Thailand by Supparapinyo *et al*, 6 of 8 patients who were treated with Am‐ photericn B responded well [61]. Nevertheless, 6 of 9 patients who were treated with 400 mg itraconazole for eight weeks also well responded [61]. Unfortunately, 4 patients died before treatment started [61]. *Penicillium marneffei* infection may become more common as HIV-in‐ fection/AIDS move into rural areas as with melioidosis [32].

#### *4.5.5. Pneumocystis jeroveci (carinii) pneumonia (Pulmonary pneumocystosis)*

Currently, the taxonomy of *Pneumocystis jeroveci (carinii)* is in question, but recent data dem‐ onstrated it is closely related to fungus [62]. Generally, *Pneumocystis jeroveci (carinii)* is a ubiquitous microorganism found every region of the world [63]. During the course of HIV disease/AIDS, 75% of the patients may develop *Pneumocystis jeroveci (carinii)* pneumonia (PCP) [64]. A previous study by Cheepsattayakorn *et al* at the 10th Zonal Tuberculosis and Chest Disease center, Chiang Mai, Thailand between 1999 and 2000 among 49 HIV-infected/ AIDS patients who had clinical manifestations and chest roentgenographic findings compat‐ ible with PCP revealed that only one patient demonstrated induced sputum-reverse tran‐ scriptase polymerase chain reaction (RT-PCR)- confirmed PCP whereas two patients were confirmed by blood RT-PCR [65]. Nevertheless, the frequency of PCP is quite different in tropical countries [66]. Blaser *et al* reported that 20% of PCP occurred among HIV-infected/ AIDS individuals native to the tropics (35%) was significantly lower than for HIV-infected/ AIDS individuals in more developed countries (73%) [66]. PCP has been detected in 37% of AIDS patients of African origin in the USA and in 14-24% of African patients with AIDS treated in Europe [67]. The question is whether the exposure to *Pneumocystis jeroveci (carinii)* occurred in Africa or after leaving is not known. A previous study from Zimbabwe reported that of 50 HIV-infected/AIDS patients with acute interstitial pneumonia, 17 and 16 were di‐ agnosed PCP and TB, respectively [68]. By using sputum induction with hypertonic saline, researchers in Tanzania reported that 3 of 83 specimens (3-6%) were positive for *Pneumocys‐ tis jeroveci (carinii)* [69]. A number of previous studies in 229 AIDS cases from Haiti indicated that PCP was detected in only 7% of 131 cases compared with 71% of the first 80 AIDS pa‐ tients noted at the New York Hospital in New York City, USA [70]. Chequer *et al* reported their study in Brazil of 2,135 adult AIDS patients and demonstrated that 425 cases (20%) were diagnosed PCP whereas PCP plus another infection was detected in 265 cases (12%) [71] whereas 45% of homosexual urban AIDS patients in southern Brazil were diagnosed PCP [72]. The clinical and roentgenographic presentations of PCP are likely to be similar among the different regions [68]. Nevertheless, the frequent occurrence of TB in developing countries makes differentiation of the two diseases difficult [68], but in one study, the clini‐ cal picture most consistent with PCP was a respiratory rate of over 40/minute [68]. In con‐ trast, the coarse reticulonodular infiltrates on the chest roentgenogram is most likely to be TB [68]. Currently, the treatment of choice for PCP is trimethoprim-sulphamethoxazole [32]. Other alternative antipneumocystis drugs are often not available in the tropical countries [32]. It has been postulated that HIV-infected/AIDS patients in the tropics die before they be‐ come immunocompromised enough to develop PCP [54, 73, 74].

#### **4.6. HIV-infection/AIDS-related parasitic pneumonia**

#### *4.6.1. Pulmonary strongyloidiasis*

day) was effective in preventing future disease dissemination for Rwandese patients with isolated pulmonary cryptococcosis [56]. Fluconazole (400-800 mg/day) has been shown to be effective as primary treatment as well as long-term therapy (200- 400 mg/day) [50]. In the USA, the drug of choice for treatment of cryptococcosis is amphotericin B, with or without flucytosine [50]. Nevertheless, these antimicrobials are frequently not available in tropical

Paracoccidioidomycosis is caused by the dimorphic fungus *Paracoccidioides brasiliensis* [58]*.* The patients with paracoccidioidomycosis may present with cutaneous form, isolated pul‐ monary involvement, or disseminated form [58]. Most patients present with disseminated involvement [58]. Only few cases involving HIV-1 infection have been reported despite its endemicity [58]. The chest roentgenographic findings demonstrate notable diffuse reticulo‐ nodular infiltrates, and sometimes with hilar adenopathy [59]. Patients have been success‐ fully treated with various regimens including amphotericin B, imidazole compounds, and sulphadiazine [60]. Itraconazole (100 mg/day) appears to be more effective than ketocona‐ zole (200-400 mg/day) which has been successfully used to treat paracoccidioidomycosis in immunocompetent patients with unknown treatment duration [60]. Nevertheless, the rec‐ ommended treatment duration is 6 to 18 months [60]. At least two patients have been placed on suppressive therapy with sulphadiazine (1-6 g/day) for lifelong prophylaxis with good

This disease caused by the usual dimorphic fungus, *Penicillium marneffei*, both in normal and immunocompromised hosts [61]. This fungus is endemic to southeast Asia and southern China [61]. Most cases have been reported as a systemic mycoses [61]. A previous study from Thailand demonstrated that 11 of the 21 patients had a cough as their presentation [61]. Of the 6 cases with abnormal chest roentgenographic findings, 3 showed diffuse reticulo‐ nodular infiltrates, 2 had localized interstitial infiltrates, and 1 had a focal alveolar infiltrate [61]. Definite diagnosis is usually made from cultures of blood, bone marrow, or skin biopsy [61]. The current treatment of choice is 6-8 weeks of Amphotericin B (40 mg/kg) [32]. In in above study in Thailand by Supparapinyo *et al*, 6 of 8 patients who were treated with Am‐ photericn B responded well [61]. Nevertheless, 6 of 9 patients who were treated with 400 mg itraconazole for eight weeks also well responded [61]. Unfortunately, 4 patients died before treatment started [61]. *Penicillium marneffei* infection may become more common as HIV-in‐

Currently, the taxonomy of *Pneumocystis jeroveci (carinii)* is in question, but recent data dem‐ onstrated it is closely related to fungus [62]. Generally, *Pneumocystis jeroveci (carinii)* is a ubiquitous microorganism found every region of the world [63]. During the course of HIV

fection/AIDS move into rural areas as with melioidosis [32].

*4.5.5. Pneumocystis jeroveci (carinii) pneumonia (Pulmonary pneumocystosis)*

countries [50].

330 HLA and Associated Important Diseases

early results [60].

*4.5.4. Pulmonary penicillosis*

*4.5.3. Pulmonary paracoccidioidomycosis*

Very few parasitic diseases have been reported to cause pneumonia in HIV- infected/AIDS patients [32]. A helminth, *Strongyloides stercoralis* which is commonly found in many tropical and subtropical areas, has occasionally been reported as the cause of pulmonary disease [32]. The prevalence of this helminth in stool specimen varies from region to region as the following : 26-48% in subsahara Africa, 15-82% in Brazil, 1-16% in Ecuador, and 4-40% in the USA [75]. Although the prevalence of strongyloides infection in southeast Asia is high, but no cases have been reported in the English language literature [32]. There have been rela‐ tively few cases reported of helminth infection in AIDS patients in the tropics despite its high prevalence [32]. In a previous study in Brazil, 10% of 100 AIDS patients were infected with *Strongyloides stercoralis* [76] whereas in a study in Zambia, 6% of 63 HIV-infected pa‐ tients with chronic diarrhea were infected with *Strongyloides stercoralis* [77]. The parasitic fe‐ males live in the mucous membrane (wall) of small intestine of humans, particularly in the lamina propria of the duodenum and proximal jejunum whereas the parasitic males remain in the lumen of the bowel and they have no capability to penetrate the mucous membrane [78]. The rhabditiform larvae that emanating from the eggs pierce the mucous membrane and reach the lumen of the bowel [78]. These larvae are then passed with feces and can pen‐ etrate the intestinal epithelium or perianal skin without leaving the host by metamorphos‐ ing into filariform larvae in the lumen of small intestine [78]. This contributes to autoinfection and persistence of infection for 20 to 30 years in individuals who have left the endemic regions [79]. Most patients with hyperinfection present with cough, fever, and breath shortness and usually diffuse pulmonary infiltrates [80]. The definite diagnosis is identifying the helminth in the respiratory specimens or stool [80]. Previous reports demon‐ strated that at least two cases with strongyloides hyperinfection had concomitant PCP [81, 82]. In a previous review of the literature revealed that only surviving patients were treated with thiabendazole, 25 mg/kg twice a day for five days with three courses 10 days apart fol‐ lowed by monthly course of thiabendazole whereas the duration of treatment in HIV-1 in‐ fected individual is unknown [82]. Generally, most patients have died directly or indirectly from their strongyloides hyperinfection [82]. It seem cautious to treat any patient who is in‐ fected with *Strongyloides stercoralis* detected in the stool despite the rarity of clinically signifi‐ cant strongyloides infection in HIV-infected/AIDS patients [82].

fler's syndrome which is a self-limiting lung inflammation and is associated with blood and pulmonary eosinophilia, particularly childhood ascariasis [87, 88]. This syndrome can occur as a result of exposure to various drugs. Clinical Presentation may vary from malaise, fever, loss of appetite, myalgia, and headache [87, 88] to respiratory symptoms which include spu‐ tum-productive cough, chest pain, hemoptysis, shortness of breath, and wheezing [89]. Chest roentgenographic findings usually demonstrate peripherally basal opacities, but occa‐ sionally show unilateral, bilateral, transient, migratory, non-segmental opacities of various

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

333

*Ancylostoma duodenale* can live only one year [91, 92]. Female *Ancylostoma duodenale* produces 10,000 to 30,000 eggs per day [91, 92]. Man is the only definite host [91, 92]. *Ancylostoma duo‐ denale* larvae can enter the human host via the oral route in addition to the entry through the skin and reach pulmonary circulation through the lymphatics and venules [91]. *Ancylostoma duodenale* larvae can developmentally get arrested in the intestine or muscle and restart de‐ velopment when environmental conditions become favorable [93]. Bronchitis and bronchop‐ neumonia can occur when the larvae break through the pulmonary capillaries to enter the alveolar spaces [32, 91, 92]. Pulmonary larval migration can develop peripheral blood eosi‐ nophilia [32, 91, 92]. Hookworm larvae can release a family of protein called " ancylostomasecreted proteins (ASP) " [32, 91, 92] and can secrete low-molecular weight polypeptides which inhibit clotting factor Xa and tissue factor VIIa [94]. During pulmonary larval migra‐ tion, the patients may present with cough, fever, wheezing, and transient pulmonary infil‐ trates that is associated with blood and pulmonary eosinophilia [32]. Both albendazole (single dose of 400 mg) and mebendazole (100 mg twice daily for three days) are drug of choice for treatment of hookworm [32]. Pyrantel pamoate (single dose of 11 mg/kg with maximum dose of 1 g, orally) is an alternative drug of choice [32]. A previous study re‐

*Necator americanus* larvae can infect human only through the skin [91]. The larvae reach the lungs same mechanisms as the *Ancylostoma duodenale* [32]. The interval between the time of skin penetration and laying of eggs by adult worms is about six weeks [32]. Bronchitis and bronchopneumonia can occur when the larvae break through the pulmonary capillaries to enter the alveoli [32]. Drugs of choice for treatment of *Necator americanus* are the same as the

In Asia, nearly 20 million people are infected with *Paragonimus* species such as *Paragonimus westernmani* which is the main species in humans, *Paragonimus mexicanus*, *Paragonimus africa‐*

vealed that ivermectin can effectively treat hookworm infections [32].

drugs of choice for treatment of *Ancylostoma duodenale* [32].

sizes [90].

*4.6.3. Pulmonary ancylostomiasis*

*4.6.3.1. Ancylostoma duodenale*

*4.6.3.2. Necator americanus*

*4.6.4. Pulmonary paragonimiasis*

#### *4.6.2. Pulmonary ascariasis*

*Ascaris lumbricoides* is the most common intestinal helminthic infection [83]. Both fertilized and unfertilized eggs are passed in the feces and released in the soil [84]. Infection occurs through soil contamination of hand or food with eggs and then swallowed [84]. The eggs hatch into larvae in the small bowel, call " first stage ", then moult into second-stage larvae in the lumen of the small bowel. The second-stage larvae penetrate the wall of the intestine and migrate via lymphatics and capillaries to the hepatic circulation and to the right side of the heart and then reach the lungs [84]. The second-stage larvae larvae moult twice more in the alveoli to produce third- and fourth-stage larvae. The fourth-stage larvae which are formed 14 days after ingestion migrate upward to the trachea and then are swallowed to reach back the small bowel [84]. The fourth-stage larvae take approximately 10 days for mi‐ gration from the lungs to the small intestine [84]. It takes 10-25 days to produce eggs after initial ingestion [84]. The migrating larvae can induce tissue- and lung- granuloma forma‐ tion with macrophages, neutrophils, and eosinophils [85]. This may produce a hypersensi‐ tivity in the lungs and result in peribronchial inflammation, increased bronchial mucus production and finally, bronchospasm [85]. *Ascaris lumbricoides* can produces both specific and polyclonal IgE [85]. Elevation of IgG4 levels in patients with ascariasis have also been reported [86]. Symptomatic pulmonary involvement may range from mild cough to a Lof‐ fler's syndrome which is a self-limiting lung inflammation and is associated with blood and pulmonary eosinophilia, particularly childhood ascariasis [87, 88]. This syndrome can occur as a result of exposure to various drugs. Clinical Presentation may vary from malaise, fever, loss of appetite, myalgia, and headache [87, 88] to respiratory symptoms which include spu‐ tum-productive cough, chest pain, hemoptysis, shortness of breath, and wheezing [89]. Chest roentgenographic findings usually demonstrate peripherally basal opacities, but occa‐ sionally show unilateral, bilateral, transient, migratory, non-segmental opacities of various sizes [90].

#### *4.6.3. Pulmonary ancylostomiasis*

tively few cases reported of helminth infection in AIDS patients in the tropics despite its high prevalence [32]. In a previous study in Brazil, 10% of 100 AIDS patients were infected with *Strongyloides stercoralis* [76] whereas in a study in Zambia, 6% of 63 HIV-infected pa‐ tients with chronic diarrhea were infected with *Strongyloides stercoralis* [77]. The parasitic fe‐ males live in the mucous membrane (wall) of small intestine of humans, particularly in the lamina propria of the duodenum and proximal jejunum whereas the parasitic males remain in the lumen of the bowel and they have no capability to penetrate the mucous membrane [78]. The rhabditiform larvae that emanating from the eggs pierce the mucous membrane and reach the lumen of the bowel [78]. These larvae are then passed with feces and can pen‐ etrate the intestinal epithelium or perianal skin without leaving the host by metamorphos‐ ing into filariform larvae in the lumen of small intestine [78]. This contributes to autoinfection and persistence of infection for 20 to 30 years in individuals who have left the endemic regions [79]. Most patients with hyperinfection present with cough, fever, and breath shortness and usually diffuse pulmonary infiltrates [80]. The definite diagnosis is identifying the helminth in the respiratory specimens or stool [80]. Previous reports demon‐ strated that at least two cases with strongyloides hyperinfection had concomitant PCP [81, 82]. In a previous review of the literature revealed that only surviving patients were treated with thiabendazole, 25 mg/kg twice a day for five days with three courses 10 days apart fol‐ lowed by monthly course of thiabendazole whereas the duration of treatment in HIV-1 in‐ fected individual is unknown [82]. Generally, most patients have died directly or indirectly from their strongyloides hyperinfection [82]. It seem cautious to treat any patient who is in‐ fected with *Strongyloides stercoralis* detected in the stool despite the rarity of clinically signifi‐

*Ascaris lumbricoides* is the most common intestinal helminthic infection [83]. Both fertilized and unfertilized eggs are passed in the feces and released in the soil [84]. Infection occurs through soil contamination of hand or food with eggs and then swallowed [84]. The eggs hatch into larvae in the small bowel, call " first stage ", then moult into second-stage larvae in the lumen of the small bowel. The second-stage larvae penetrate the wall of the intestine and migrate via lymphatics and capillaries to the hepatic circulation and to the right side of the heart and then reach the lungs [84]. The second-stage larvae larvae moult twice more in the alveoli to produce third- and fourth-stage larvae. The fourth-stage larvae which are formed 14 days after ingestion migrate upward to the trachea and then are swallowed to reach back the small bowel [84]. The fourth-stage larvae take approximately 10 days for mi‐ gration from the lungs to the small intestine [84]. It takes 10-25 days to produce eggs after initial ingestion [84]. The migrating larvae can induce tissue- and lung- granuloma forma‐ tion with macrophages, neutrophils, and eosinophils [85]. This may produce a hypersensi‐ tivity in the lungs and result in peribronchial inflammation, increased bronchial mucus production and finally, bronchospasm [85]. *Ascaris lumbricoides* can produces both specific and polyclonal IgE [85]. Elevation of IgG4 levels in patients with ascariasis have also been reported [86]. Symptomatic pulmonary involvement may range from mild cough to a Lof‐

cant strongyloides infection in HIV-infected/AIDS patients [82].

*4.6.2. Pulmonary ascariasis*

332 HLA and Associated Important Diseases

### *4.6.3.1. Ancylostoma duodenale*

*Ancylostoma duodenale* can live only one year [91, 92]. Female *Ancylostoma duodenale* produces 10,000 to 30,000 eggs per day [91, 92]. Man is the only definite host [91, 92]. *Ancylostoma duo‐ denale* larvae can enter the human host via the oral route in addition to the entry through the skin and reach pulmonary circulation through the lymphatics and venules [91]. *Ancylostoma duodenale* larvae can developmentally get arrested in the intestine or muscle and restart de‐ velopment when environmental conditions become favorable [93]. Bronchitis and bronchop‐ neumonia can occur when the larvae break through the pulmonary capillaries to enter the alveolar spaces [32, 91, 92]. Pulmonary larval migration can develop peripheral blood eosi‐ nophilia [32, 91, 92]. Hookworm larvae can release a family of protein called " ancylostomasecreted proteins (ASP) " [32, 91, 92] and can secrete low-molecular weight polypeptides which inhibit clotting factor Xa and tissue factor VIIa [94]. During pulmonary larval migra‐ tion, the patients may present with cough, fever, wheezing, and transient pulmonary infil‐ trates that is associated with blood and pulmonary eosinophilia [32]. Both albendazole (single dose of 400 mg) and mebendazole (100 mg twice daily for three days) are drug of choice for treatment of hookworm [32]. Pyrantel pamoate (single dose of 11 mg/kg with maximum dose of 1 g, orally) is an alternative drug of choice [32]. A previous study re‐ vealed that ivermectin can effectively treat hookworm infections [32].

#### *4.6.3.2. Necator americanus*

*Necator americanus* larvae can infect human only through the skin [91]. The larvae reach the lungs same mechanisms as the *Ancylostoma duodenale* [32]. The interval between the time of skin penetration and laying of eggs by adult worms is about six weeks [32]. Bronchitis and bronchopneumonia can occur when the larvae break through the pulmonary capillaries to enter the alveoli [32]. Drugs of choice for treatment of *Necator americanus* are the same as the drugs of choice for treatment of *Ancylostoma duodenale* [32].

#### *4.6.4. Pulmonary paragonimiasis*

In Asia, nearly 20 million people are infected with *Paragonimus* species such as *Paragonimus westernmani* which is the main species in humans, *Paragonimus mexicanus*, *Paragonimus africa‐* *nus*, *Paragonimus miyazakii*, *Paragonimus phillipinensis*, *Paragonimus kellicotti*, *Paragonimus skrjabini*, *Paragonimus heterotremus*, and *Paragonimus uterobilateralis* [95-97]. Paragonimiasis is a food-borne zoonoses [32]. Humans get *Paragonimus* species when ingest raw crayfishes or crabs infected with infective metacercariae [95]. The parasite from the human gut passes through several organs and tissues to reach the lungs [95]. Adult worm live in the lungs and the eggs are voided in the sputum or feces [95]. Pulmonary paragonimiasis manifests as chronic cough, hemoptysis, chest pain, and fever [98]. Pneumothorax or pleural effusion is an important manifestation in paragonimiasis [99]. Chest roentgenographs may demon‐ strate infiltrates, nodules, and cavities [100]. The parasitic eggs can be shown in sputum specimens, bronchoalveolar lavage fluid or lung biopsy specimens [32].Peripheral blood eo‐ sinophilia and elevated serum IgE levels are demonstrated in more than 80% of cases with paragonimiasis [95, 99]. *Paragonimus westernmani* adult excretory-secretory products are composed of cysteine proteases which are involved in immunological reactions during para‐ sitic infection [101, 102]. Immunoglobulin G4 antibodies to an excretory-secretory product of *Paragonimus heterotremus* had accuracy, sensitivity, specificity, and positive and negative predictive values of 97.6%, 100%, 96.9%, 90%, and 100%, respectively [103]. Paragonimiasis can be treated with praziquantel 75 mg/kg/day for three days), triclabendazole (20 mg/kg in two equal doses), niclofolan (2 mg/kg as a single dose), or bithionol (30 to 40 mg/kg in 10 days on alternative days) [95, 104, 105].

*4.6.6. Pulmonary hydatid disease*

and pneumonectomy [122-124].

is analgesics and corticosteroids [32].

*4.6.7. Pulmonary trichinellosis*

Human hydatid disease is caused by *Echinococcus multilocularis* and *Echinococcus granulosus* [32]. Hydatid cysts are mainly formed in the lungs and liver [32]. Pulmonary alveolar echino‐ coccosis (AE) is caused by hematogenous spreading from hepatic lesions [114]. The adult *Echinococcus granulosus* resides mainly in the small gut of the dogs [32]. Humans are infected by ingestion of parasitic eggs excreted in the feces of the dogs [32]. Clinical pulmonary manifestations include cough, dyspnea, chest pain, and fever [32]. Rupture of hydatid cysts into a bronchus may result in expectoration of cystic fluid containing parasite membrane, hemoptysis, asthma-liked symptoms, respiratory distress, persistent pneumonia, anaphylactic shock, and sepsis [115, 116] and elevation of IgG and eosinophilia [117]. Immunodiagnostic tests using purified *Echinococcus granulosus* antigens have preferable sensitivity and specificity for the diagnosis of AE [118]. Chest roentgenographs demonstrate solitary or multiple round opacificaties mimicking lung tumors [119]. It has been experimentally revealed that magnetic resonance imaging can detect early pulmonary AE [120]. Many year-treatment with meben‐ dazole, praziquantel or albendazole is useful, particularly in inoperably recurrent and multiple cysts, but treatment of hydatid cyst is primary surgical [121]. The treatment of AE is radical surgical resection of entire parasitic lesion [121] but should avoid segmentectomy, lobectomy,

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

335

The most important species that infect humans is *Trichinella spiralis*[125]. Humans get parasitic infection from ingestion of raw and infected pig's muscle containing larval trichinellae [126]. The larvae develop into adults in the duodenum and jejunum [126]. The larvae undergo encystment in the muscle and a host capsule develops around the larvae and later on may get calcified [126]. Clinical pulmonary features include cough, dyspnea, and pulmonary infiltrates on the chest roentgenographs [127]. The important laboratory findings are elevation of serum aminotransferase, serum adolase, serum lactate dehydrogenase, and serum creatine phospho‐ kinase, leukocytosis, and eosinophilia [127]. An enzyme-linked immunosorbent assay (ELISA) for identification of anti-*Trichinella* antibodies using excretory-secretory antigens may be useful in the diagnosis of *Trichinella spiralis* infection [128], a definite diagnosis can be per‐ formed by muscle biopsy (preferably deltoid muscle) [127]. Treatment of choice is with mebendazole, 200 to 400 mg, three times a day for three days followed by 400 to 500 mg, three times a day for 10 days [32]. The alternative drug of choice is albendazole, 400 mg per day for three days followed by 800 mg per day for 15 days [32]. Symptomatic treatment of trichinosis

**5. Filarial parasites — Related tropical pulmonary eosinophilia and HLA**

This syndrome results from immunological hyperresponsiveness to human filarial parasites, *Wuchereria bancrofti* and *Brugia malayi* [129]. Tropical pulmonary eosinophilia (TPE) is one of the main causes of pulmonary eosinophilia in the tropical countries and is prevalent in filarial

#### *4.6.5. Pulmonary schistosomiasis*

*Schistosoma* species that cause human disease are *Schistosoma hematobium*, *Schistosoma japoni‐ cum*, and *Schistosoma mansoni* [106]. The schistosome eggs are passed in feces (*Schistosoma ja‐ ponicum* and *Schistosoma mansoni*) or in urine (*Schistosoma hematobium*) [32]. The infective cercariae in water are ingested to penetrate the human gut or penetrate human skin and fi‐ nally reside at the mesenteric beds (*Schistosoma japonicum* and *Schistosoma mansoni*) and the urinary bladder vesicle beds (*Schistosoma hematobium*) [32]. Pulmonary schistosomiasis can clinically present as acute or chronic form [32]. Acute manifestations, called " Katayama syndrome " can develop three to eight weeks after skin penetration [107, 108]. The acute form presents with dry cough, wheezing, shortness of breath, chill, fever, weight loss, ab‐ dominal pain, diarrhea, urticarial, myalgia [108, 109], and small pulmonary nodules in chest roentgenographs or computed tomography in immunocompromised patients [110]. Patients with chronic form present with pulmonary hypertension and cor-pulmonale [111, 112] whereas massive hemoptysis and lobar consolidation and collapse have been reported [113]. Hepatosplenomegaly due to portal hypertension has been reported in patients infected with *Schistosoma japonicum* and *Schistosoma mansoni* [106]. In chronic form, peripheral blood eosi‐ nophilia with mild leukocytosis, IgE levels, and abnormal liver function test are reported [106]. Acute and chronic schistosomiasis can be treated with corticosteroids alone followed by praziquantel (20-30 mg/kg orally in two doses within 12 hours) and then praziquantel is repeated several weeks later to eradicate the adult flukes [106]. Acute form can be treated with artemether, an artemisinin derivative [106].

#### *4.6.6. Pulmonary hydatid disease*

*nus*, *Paragonimus miyazakii*, *Paragonimus phillipinensis*, *Paragonimus kellicotti*, *Paragonimus skrjabini*, *Paragonimus heterotremus*, and *Paragonimus uterobilateralis* [95-97]. Paragonimiasis is a food-borne zoonoses [32]. Humans get *Paragonimus* species when ingest raw crayfishes or crabs infected with infective metacercariae [95]. The parasite from the human gut passes through several organs and tissues to reach the lungs [95]. Adult worm live in the lungs and the eggs are voided in the sputum or feces [95]. Pulmonary paragonimiasis manifests as chronic cough, hemoptysis, chest pain, and fever [98]. Pneumothorax or pleural effusion is an important manifestation in paragonimiasis [99]. Chest roentgenographs may demon‐ strate infiltrates, nodules, and cavities [100]. The parasitic eggs can be shown in sputum specimens, bronchoalveolar lavage fluid or lung biopsy specimens [32].Peripheral blood eo‐ sinophilia and elevated serum IgE levels are demonstrated in more than 80% of cases with paragonimiasis [95, 99]. *Paragonimus westernmani* adult excretory-secretory products are composed of cysteine proteases which are involved in immunological reactions during para‐ sitic infection [101, 102]. Immunoglobulin G4 antibodies to an excretory-secretory product of *Paragonimus heterotremus* had accuracy, sensitivity, specificity, and positive and negative predictive values of 97.6%, 100%, 96.9%, 90%, and 100%, respectively [103]. Paragonimiasis can be treated with praziquantel 75 mg/kg/day for three days), triclabendazole (20 mg/kg in two equal doses), niclofolan (2 mg/kg as a single dose), or bithionol (30 to 40 mg/kg in 10

*Schistosoma* species that cause human disease are *Schistosoma hematobium*, *Schistosoma japoni‐ cum*, and *Schistosoma mansoni* [106]. The schistosome eggs are passed in feces (*Schistosoma ja‐ ponicum* and *Schistosoma mansoni*) or in urine (*Schistosoma hematobium*) [32]. The infective cercariae in water are ingested to penetrate the human gut or penetrate human skin and fi‐ nally reside at the mesenteric beds (*Schistosoma japonicum* and *Schistosoma mansoni*) and the urinary bladder vesicle beds (*Schistosoma hematobium*) [32]. Pulmonary schistosomiasis can clinically present as acute or chronic form [32]. Acute manifestations, called " Katayama syndrome " can develop three to eight weeks after skin penetration [107, 108]. The acute form presents with dry cough, wheezing, shortness of breath, chill, fever, weight loss, ab‐ dominal pain, diarrhea, urticarial, myalgia [108, 109], and small pulmonary nodules in chest roentgenographs or computed tomography in immunocompromised patients [110]. Patients with chronic form present with pulmonary hypertension and cor-pulmonale [111, 112] whereas massive hemoptysis and lobar consolidation and collapse have been reported [113]. Hepatosplenomegaly due to portal hypertension has been reported in patients infected with *Schistosoma japonicum* and *Schistosoma mansoni* [106]. In chronic form, peripheral blood eosi‐ nophilia with mild leukocytosis, IgE levels, and abnormal liver function test are reported [106]. Acute and chronic schistosomiasis can be treated with corticosteroids alone followed by praziquantel (20-30 mg/kg orally in two doses within 12 hours) and then praziquantel is repeated several weeks later to eradicate the adult flukes [106]. Acute form can be treated

days on alternative days) [95, 104, 105].

with artemether, an artemisinin derivative [106].

*4.6.5. Pulmonary schistosomiasis*

334 HLA and Associated Important Diseases

Human hydatid disease is caused by *Echinococcus multilocularis* and *Echinococcus granulosus* [32]. Hydatid cysts are mainly formed in the lungs and liver [32]. Pulmonary alveolar echino‐ coccosis (AE) is caused by hematogenous spreading from hepatic lesions [114]. The adult *Echinococcus granulosus* resides mainly in the small gut of the dogs [32]. Humans are infected by ingestion of parasitic eggs excreted in the feces of the dogs [32]. Clinical pulmonary manifestations include cough, dyspnea, chest pain, and fever [32]. Rupture of hydatid cysts into a bronchus may result in expectoration of cystic fluid containing parasite membrane, hemoptysis, asthma-liked symptoms, respiratory distress, persistent pneumonia, anaphylactic shock, and sepsis [115, 116] and elevation of IgG and eosinophilia [117]. Immunodiagnostic tests using purified *Echinococcus granulosus* antigens have preferable sensitivity and specificity for the diagnosis of AE [118]. Chest roentgenographs demonstrate solitary or multiple round opacificaties mimicking lung tumors [119]. It has been experimentally revealed that magnetic resonance imaging can detect early pulmonary AE [120]. Many year-treatment with meben‐ dazole, praziquantel or albendazole is useful, particularly in inoperably recurrent and multiple cysts, but treatment of hydatid cyst is primary surgical [121]. The treatment of AE is radical surgical resection of entire parasitic lesion [121] but should avoid segmentectomy, lobectomy, and pneumonectomy [122-124].

#### *4.6.7. Pulmonary trichinellosis*

The most important species that infect humans is *Trichinella spiralis*[125]. Humans get parasitic infection from ingestion of raw and infected pig's muscle containing larval trichinellae [126]. The larvae develop into adults in the duodenum and jejunum [126]. The larvae undergo encystment in the muscle and a host capsule develops around the larvae and later on may get calcified [126]. Clinical pulmonary features include cough, dyspnea, and pulmonary infiltrates on the chest roentgenographs [127]. The important laboratory findings are elevation of serum aminotransferase, serum adolase, serum lactate dehydrogenase, and serum creatine phospho‐ kinase, leukocytosis, and eosinophilia [127]. An enzyme-linked immunosorbent assay (ELISA) for identification of anti-*Trichinella* antibodies using excretory-secretory antigens may be useful in the diagnosis of *Trichinella spiralis* infection [128], a definite diagnosis can be per‐ formed by muscle biopsy (preferably deltoid muscle) [127]. Treatment of choice is with mebendazole, 200 to 400 mg, three times a day for three days followed by 400 to 500 mg, three times a day for 10 days [32]. The alternative drug of choice is albendazole, 400 mg per day for three days followed by 800 mg per day for 15 days [32]. Symptomatic treatment of trichinosis is analgesics and corticosteroids [32].

### **5. Filarial parasites — Related tropical pulmonary eosinophilia and HLA**

This syndrome results from immunological hyperresponsiveness to human filarial parasites, *Wuchereria bancrofti* and *Brugia malayi* [129]. Tropical pulmonary eosinophilia (TPE) is one of the main causes of pulmonary eosinophilia in the tropical countries and is prevalent in filarial endemic regions of the world particularly Southeast Asia [129, 130]. Clinical findings are cough, fever, chest pain, and body weight loss in association with massive blood eosinophilia [131]. Chest roentgenographs demonstrate military infiltrates of both lungs mimic military TB [132]. Additionally, there may be prominent hila with heavy vascular markings [133-136], but 20% of cases present with normal chest roentgenographs [137]. Some previous studies of computed tomographic scan of the chest demonstrated air trapping, mediastinal lymphaden‐ opathy, calcification, and bronchiectasis [138]. At least 120 million people are globally infected with mosquito-borne lymphatic filariasis [137], but only less than 1% of filarial infection causes TPE [139] whereas various studies have demonstrated that filarial infection is the cause of TPE [129, 140]. A positive immediate reaction to intradermal skin tests with *Dirofilaria immitis* antigens have been demonstrated in patients with TPE [141]. Microfilariae, anatomical features of *Wuchereria bancrofti* had demonstrated in the lungs, liver, and lymph nodes of the patients with TPE [142-144], but are rarely identified in the blood [142]. A recent study revealed that the CD45RA+ and CD45RA- effector cells in patients with chronic lymphatic filarial infection demonstrated a reduced activation state based on their lower expression of *HLA-DR*, con‐ trasting with findings identified in patients with HIV-1 infection [145]. An inverse correlation between the percentage of CD8+ HLA-DR+ lymphocytes pokeweed mitogen-induced prolif‐ eration was observed [146]. These findings indicated that activated CD8+ - T lymphocytes may be involved in the pathogenesis of chronically obstructive lymphatic form of filariasis [146]. A previous study conducted by Sasisekhar *et al* demonstrated that monocytes from microfilare‐ mic (MF) patients revealed an inability to respond to lipopolysaccharide compared to mono‐ cytes from endemic normal individuals of from patients with lymphedema [147]. Serum from MF patients demonstrated reduction of adherence and spreading of normal monocytes which was a finding not observed with serum from other clinical individuals [147]. Surprisingly, there was a significant correlation between the adherence of normal lymphocytes and the production of interleukin (IL)-1β with spontaneous secretion of IL-10 [147]. The effects noted were not a result of diminished viability or alteration in the expression of the cell surface markers *HLA-DR* and CD14 [147]. This study indicates that monocyte function is dampened in MF patients [147]. A previous study in Sri Lanka and India demonstrated that 30% of Sri Lankan patients with elephantiasis and 28% of Southern Indian patients with elephantiasis were significantly associated with *HLA-B\*15* compared to 4% of Sri Lankan controls and 10% of Southern Indian controls [148]. Filarial specific IgG and IgE concentration elevation have been observed in TPE [149]. Peripheral basophils from patients with TPE was released more greater amounts of histamine when they were challenged with *Wuchereria* or *Brugia* antigens than with *Dirofilar‐ ia* antigen [149]. This indicated that TPE resulted from immunological hyperresponsiveness to human filarial parasites [149]. Leukocyte adhesion phenomenon in sera from patients with TPE using *Wuchereria bancrofti* revealed maximal positive results compared with *Dirofilaria immitis* and *Dirofilaria repens* [150]. Demonstration of living adult *Wuchereria bancrofti* in the lymphatic vessels of the spermatic cord of the patients with TPE is evidenced by ultrasound examination [151] and biopsy of a lump in the spermatic cord shows degenerating adult female filarial worm with uteri full of microfilariae [152]. There is a marked reduction of filarialspecific IgG and IgE levels in the lung epithelial lining fluid [153] and roentgenological improvement [154, 155] after 6-14 days of therapy with dethylcarbamazine citrate (DEC). The

standard treatment recommended by the World Health Organization is oral DEC (6 mg/kg/ day) for three weeks [156]. The usefulness of DEC in the treatment of TPE further focuses

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

337

Four types of malarial parasites (*Plasmodium falciparum*, *Plasmodium malariae*, *Plasmodium vi‐ vax*, and *Plasmodium ovale*), the protozoa of the genus *Plasmodium* causes malaria and is pri‐ marily transmitted by the bite of an infected female *Anopheles* mosquito to infect humans [159]. A previous study in a Thai population demonstrated that the allele frequencies of *HLA-B\*46*, *-B\*56*, and *-DRB1\*1001* were statistically different between non- cerebral severe malaria and cerebral malaria, between mild malaria and non-cerebral malaria, and mild ma‐ laria and cerebral malaria, respectively [160]. A recent study revealed that the NK cell reper‐ toire shaped by the *KIR2DL3-HLA-C1* interaction demonstrates certain functional responses that facilitates the development of cerebral malaria [161]. The frequency of the *KIR2DL3- HLA-C1* combination was found to be significantly lower in malaria high-endemic popula‐ tions [161]. This indicates that natural selection has reduced the frequency of the *KIR2DL3- HLA-C1* combination in in malaria high-endemic populations because of the propensity of interaction between *KIR2DL3* and *C1* to favor development of cerebral malaria [161]. Young *et al* conducted a study in Mali and Gambia and reported that either malaria parasite types cp26 or cp29 were found to be less, not more common in Mali population with *HLA-B\*35* (37%) compared to non-*HLA-B\*35*-bearing hosts (55%) whereas 51% of *HLA-B\*35*-bearing Gambian population were infected with either cp26 or cp29 compared to 42% of non-*HLA-B\*35*-bearing hosts [162]. A previous study in West African children demonstrates that *HLA-Bw\*53*, *-DRB1\*1302*, and *-DQB1\*0501* which are common in West Africans are independently associated with protection from severe malaria [163]. *HLA-DR\*04* alleles were observed more frequently among patients with severe malaria [164]. Additionally, car‐ riers of the amino acid methionine at position 11 of the *DPA1* allele were more often infected with merozoite surface antigen (MSA)-1 K1 malaria parasites and less frequently with MSA-1 RO33 malaria parasite infection [164]. The main finding of patients with falciparum malaria which is the most deadly type of malaria infection is sequestration of erythrocytes containing mature forms of *Plasmodium falciparum* in the microvasculature of the organs and is quantified by measurement of *Plasmodium falciparum* specific histidine-rich protein 2 (PfHRP2) using a quantitative antigen-capture enzyme-linked immunosorbent assay [159]. Gas exchange is significantly impaired in patients with severe malaria [165]. The gold stand‐ ards for the diagnosis of malaria are light microscopic examination of thin and thick stained blood smears [78, 166]. Human urine and saliva PCR detection of *Plasmodium falciparum* has been introduced [166]. In severe falciparum malaria, the roentgenographic presentations in‐ clude diffuse interstitial edema, pulmonary edema, pleural effusion, and lobar consolidation [166]. Intravenous chloroquine is the drug of choice for chloroqiune-susceptible *Plasmodium falciparum* infections and those rare cases of life-threatening malaria caused by *Plasmodium*

attention on its filarial etiology [157, 158].

**6. Pulmonary malaria and HLA**

standard treatment recommended by the World Health Organization is oral DEC (6 mg/kg/ day) for three weeks [156]. The usefulness of DEC in the treatment of TPE further focuses attention on its filarial etiology [157, 158].

### **6. Pulmonary malaria and HLA**

endemic regions of the world particularly Southeast Asia [129, 130]. Clinical findings are cough, fever, chest pain, and body weight loss in association with massive blood eosinophilia [131]. Chest roentgenographs demonstrate military infiltrates of both lungs mimic military TB [132]. Additionally, there may be prominent hila with heavy vascular markings [133-136], but 20% of cases present with normal chest roentgenographs [137]. Some previous studies of computed tomographic scan of the chest demonstrated air trapping, mediastinal lymphaden‐ opathy, calcification, and bronchiectasis [138]. At least 120 million people are globally infected with mosquito-borne lymphatic filariasis [137], but only less than 1% of filarial infection causes TPE [139] whereas various studies have demonstrated that filarial infection is the cause of TPE [129, 140]. A positive immediate reaction to intradermal skin tests with *Dirofilaria immitis* antigens have been demonstrated in patients with TPE [141]. Microfilariae, anatomical features of *Wuchereria bancrofti* had demonstrated in the lungs, liver, and lymph nodes of the patients with TPE [142-144], but are rarely identified in the blood [142]. A recent study revealed that

and CD45RA- effector cells in patients with chronic lymphatic filarial infection

lymphocytes pokeweed mitogen-induced prolif‐


demonstrated a reduced activation state based on their lower expression of *HLA-DR*, con‐ trasting with findings identified in patients with HIV-1 infection [145]. An inverse correlation

be involved in the pathogenesis of chronically obstructive lymphatic form of filariasis [146]. A previous study conducted by Sasisekhar *et al* demonstrated that monocytes from microfilare‐ mic (MF) patients revealed an inability to respond to lipopolysaccharide compared to mono‐ cytes from endemic normal individuals of from patients with lymphedema [147]. Serum from MF patients demonstrated reduction of adherence and spreading of normal monocytes which was a finding not observed with serum from other clinical individuals [147]. Surprisingly, there was a significant correlation between the adherence of normal lymphocytes and the production of interleukin (IL)-1β with spontaneous secretion of IL-10 [147]. The effects noted were not a result of diminished viability or alteration in the expression of the cell surface markers *HLA-DR* and CD14 [147]. This study indicates that monocyte function is dampened in MF patients [147]. A previous study in Sri Lanka and India demonstrated that 30% of Sri Lankan patients with elephantiasis and 28% of Southern Indian patients with elephantiasis were significantly associated with *HLA-B\*15* compared to 4% of Sri Lankan controls and 10% of Southern Indian controls [148]. Filarial specific IgG and IgE concentration elevation have been observed in TPE [149]. Peripheral basophils from patients with TPE was released more greater amounts of histamine when they were challenged with *Wuchereria* or *Brugia* antigens than with *Dirofilar‐ ia* antigen [149]. This indicated that TPE resulted from immunological hyperresponsiveness to human filarial parasites [149]. Leukocyte adhesion phenomenon in sera from patients with TPE using *Wuchereria bancrofti* revealed maximal positive results compared with *Dirofilaria immitis* and *Dirofilaria repens* [150]. Demonstration of living adult *Wuchereria bancrofti* in the lymphatic vessels of the spermatic cord of the patients with TPE is evidenced by ultrasound examination [151] and biopsy of a lump in the spermatic cord shows degenerating adult female filarial worm with uteri full of microfilariae [152]. There is a marked reduction of filarialspecific IgG and IgE levels in the lung epithelial lining fluid [153] and roentgenological improvement [154, 155] after 6-14 days of therapy with dethylcarbamazine citrate (DEC). The

eration was observed [146]. These findings indicated that activated CD8+

the CD45RA+

336 HLA and Associated Important Diseases

between the percentage of CD8+ HLA-DR+

Four types of malarial parasites (*Plasmodium falciparum*, *Plasmodium malariae*, *Plasmodium vi‐ vax*, and *Plasmodium ovale*), the protozoa of the genus *Plasmodium* causes malaria and is pri‐ marily transmitted by the bite of an infected female *Anopheles* mosquito to infect humans [159]. A previous study in a Thai population demonstrated that the allele frequencies of *HLA-B\*46*, *-B\*56*, and *-DRB1\*1001* were statistically different between non- cerebral severe malaria and cerebral malaria, between mild malaria and non-cerebral malaria, and mild ma‐ laria and cerebral malaria, respectively [160]. A recent study revealed that the NK cell reper‐ toire shaped by the *KIR2DL3-HLA-C1* interaction demonstrates certain functional responses that facilitates the development of cerebral malaria [161]. The frequency of the *KIR2DL3- HLA-C1* combination was found to be significantly lower in malaria high-endemic popula‐ tions [161]. This indicates that natural selection has reduced the frequency of the *KIR2DL3- HLA-C1* combination in in malaria high-endemic populations because of the propensity of interaction between *KIR2DL3* and *C1* to favor development of cerebral malaria [161]. Young *et al* conducted a study in Mali and Gambia and reported that either malaria parasite types cp26 or cp29 were found to be less, not more common in Mali population with *HLA-B\*35* (37%) compared to non-*HLA-B\*35*-bearing hosts (55%) whereas 51% of *HLA-B\*35*-bearing Gambian population were infected with either cp26 or cp29 compared to 42% of non-*HLA-B\*35*-bearing hosts [162]. A previous study in West African children demonstrates that *HLA-Bw\*53*, *-DRB1\*1302*, and *-DQB1\*0501* which are common in West Africans are independently associated with protection from severe malaria [163]. *HLA-DR\*04* alleles were observed more frequently among patients with severe malaria [164]. Additionally, car‐ riers of the amino acid methionine at position 11 of the *DPA1* allele were more often infected with merozoite surface antigen (MSA)-1 K1 malaria parasites and less frequently with MSA-1 RO33 malaria parasite infection [164]. The main finding of patients with falciparum malaria which is the most deadly type of malaria infection is sequestration of erythrocytes containing mature forms of *Plasmodium falciparum* in the microvasculature of the organs and is quantified by measurement of *Plasmodium falciparum* specific histidine-rich protein 2 (PfHRP2) using a quantitative antigen-capture enzyme-linked immunosorbent assay [159]. Gas exchange is significantly impaired in patients with severe malaria [165]. The gold stand‐ ards for the diagnosis of malaria are light microscopic examination of thin and thick stained blood smears [78, 166]. Human urine and saliva PCR detection of *Plasmodium falciparum* has been introduced [166]. In severe falciparum malaria, the roentgenographic presentations in‐ clude diffuse interstitial edema, pulmonary edema, pleural effusion, and lobar consolidation [166]. Intravenous chloroquine is the drug of choice for chloroqiune-susceptible *Plasmodium falciparum* infections and those rare cases of life-threatening malaria caused by *Plasmodium* *vivax*, *Plasmodium malariae*, and *Plasmodium ovale* [78, 166]. A point mutation in the *Plasmodi‐ um falciparum* chloroqiune-resistance transporter (PfCRT) gene is responsible for chloro‐ qiune-resistant falciparum malaria [167] whereas diaappearance of the K76T mutation in PfCRT is associated with chloroquine susceptibility [168]. Oral artemisinin -based combina‐ tion therapies (artesunate + mefloquine, artesunate + sulfadoxine-pyrimethamine, artesunate + amodioquine, or artemether + lumefantrine) are the best antimalarial drugs [169, 170]. Ad‐ ditionally, the World Health Organization (WHO) recommends oral treatment of dihydroar‐ temisinin plus piperaquine as soon as the patients is able to take oral medication but not before a minimum of 24 hours of parenteral treatment [171]. The WHO recommended that intravenous artesunate can be used preferentially over quinine for the treatment of severe malaria caused by any *Plasmodium* species in both children and adults [172]. Oral artemisi‐ nin-based combination therapies have also demonstrated equivalent (if not better) efficacy in the treatment of uncomplicated malaria caused by all *Plasmodium* species and chloro‐ quine-resistant *Plasmodium vivax* in both children and adults [172]. Hence, conventional therapeutic regimens continue to be efficacious [172]. Insecticide-treated bed-nets in which insecticide is incorporated into the net fibers is evidenced to be the best way to prevent ma‐ laria [173]. It is demonstrated that RTS, S/ASO2, a vaccine has demonstrated promising re‐ sults in endemic areas [173].

tion reveals fever, chest pain, tender hepatomegaly, and cough are indicated pleuropulmonary amoebiasis [78]. Some patients may present with hemoptysis, expectoration of anchovy source-liked pus, respiratory distress, and shock [78]. Chest roentgenographic findings include pleural effusion, basal pulmonary involvement, and elevation of hemidiaphragm [78]. Metronidazole is the treatment of choice [183]. Diloxanide furoate, a luminal amoebiacidal drug can eliminate intestinal *Entamoeba* cysts [184]. Lactoferrin and lactoferricins, amoebicidal drugs, can be co-administered with a low dose of metronidazole to reduce metronidazole toxicity [184]. Identification of possible vaccine candidates against amoebiasis are in progres‐

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

339

Pulmonary or visceral leishmaniasis, also called " Kala azar " is caused by *Leishmania donova‐ ni* and and *Leishmania chagasi* or *infantum* [186] is transmitted by various species of *Pheboto‐ mus*, a type of sand fly [187]. *Leishmania amastigotes* can be identified in pulmonary septa, alveoli, and the BAL fluid [188, 189]. Pleural effusion, mediastinal lymphadenopathy, and pneumonitis have been reported in HIV-infected patients with visceral leishmaniasis and lung transplant patients [188, 189]. The expansion of the HIV- infection/AIDS epidemic over leishmaniasis, particularly visceral leishmaniasis endemic regions has increased the number of co-infected patients [190] indicating that visceral leishmaniasis is an opportunistic disease in HIV-infected/AIDS patients although not yet considered an AIDS-defining disease [191]. According to sharing of immune-compromising mechanisms of both infections with *Leishma‐ nia infantum* and HIV-1 that may affect the parasite control in visceral leishmaniasis co-infected patients [191]. In comparison to patients with visceral leishmaniasis alone, co-infected patients present a more severe disease with increased parasite burden, frequent relapses, and anti‐ leishmanial drug resistance [190, 192]. On the other hand, Leishmania infection can impair both the chronic immune activation and the lymphocyte depletion and can accelerate pro‐ gression to AIDS, particularly in HIV-1-infected individuals [193, 194]. Hence, serological testings for latent infection due to *Leishmania* species are indicated in the pre-transplantation screening from endemic areas [195]. A recent study in two populations from Brazil (cases) and India (controls) demonstrated that the *HLA-DRB1-HLA-DQA1 HLA* class II region strongly contributed to visceral leishmaniasis susceptibility, indicating shared risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species [196]. Several previous studies of *Leishmania donovani* in mice model demonstrated dramatic differences in visceral disease in spleens and livers in congenic mice with different H-2 haplotypes [197]. There was evidenced that noncuring and curing responses mapped to the HLA-class II molecules by using recombinant congenic mice [198] and functional analysis blocking IA or IE (corresponding to DQ and DR, respectively) molecules *in vivo* with mono‐ clonal antibodies [199]. A significant role for CD8+ T-cells has also been shown in *Leishmania donovani* [200, 201]. A previous case-control study in Tunisia demonstrated that visceral leishmaniasis was associated with *DR/DQ* class II genes but not with *TNF/LTA* or *HSP70* class III loci [202]. Associations between delayed-type hypersensitivity-positive asymptomatic

sive studies [185].

**8. Pulmonary leishmaniasis and HLA**

#### **7. Pulmonary amoebiasis and HLA**

Pulmonary amoebiasis that caused by the protozoan parasite, *Entamoeba histolytica* occurs mainly by the extension from the amoebic liver abscess [174, 175]. In a nine-year prospective study in a cohort of preschool children in Dhaka, Bangladesh demonstrated that a single amino acid polymorphism (Q223R) in the leptin receptor was associated with increased susceptibility to *Entamoeba histolytica* infection [176]. Children with two arginine alleles (223R) were nearly four times more likely to infect with *Entamoeba histolytica* as compared to those homozygous for glutamine (223Q) [176]. An *in vitro* study demonstrated that leptin signaling protected human epithelial cells from amoebic killing via a STAT3- dependent pathway [177]. It was identified that children who were heterozygous for the HLA class II *DQB1\*0601/DRB1\*1501* haplotype were more likely to *Entamoeba histolytica* negative [178]. The immune mechanism that explains why only a subset of *Entamoeba histolytica*-exposed persons develops clinical disease is not fully understood [179]. The effect of microbiota on immune response to *Entamoeba histolytica* and its virulence is not yet known [179]. The presence of cysts or trophozoites of amoeba in the stool does not imply that the disease is caused by *Entamoeba histolytica* as other two non-pathogenic species found in humans (*Entamoeba dispar* and *Entamoeba moshkovskii*) are morphologically indistinguishable, but can be rapidly, accurately, and effectively diagnosed by a single-round PCR [78, 180, 181]. Other diagnostic methods include culture of *Entamoeba histolytica*, ELISA, indirect fluorescent antibody test (IFAT), and indirect hemagglutination test (IHA) [78, 180, 181]. A combination of serological tests with identification of the parasite by PCR or antigen detection is the best diagnostic approach [182]. Active trophozoites of *Entamoeba histolytica* can be identified in sputum or pleural specimen [78]. Physical examina‐

tion reveals fever, chest pain, tender hepatomegaly, and cough are indicated pleuropulmonary amoebiasis [78]. Some patients may present with hemoptysis, expectoration of anchovy source-liked pus, respiratory distress, and shock [78]. Chest roentgenographic findings include pleural effusion, basal pulmonary involvement, and elevation of hemidiaphragm [78]. Metronidazole is the treatment of choice [183]. Diloxanide furoate, a luminal amoebiacidal drug can eliminate intestinal *Entamoeba* cysts [184]. Lactoferrin and lactoferricins, amoebicidal drugs, can be co-administered with a low dose of metronidazole to reduce metronidazole toxicity [184]. Identification of possible vaccine candidates against amoebiasis are in progres‐ sive studies [185].

### **8. Pulmonary leishmaniasis and HLA**

*vivax*, *Plasmodium malariae*, and *Plasmodium ovale* [78, 166]. A point mutation in the *Plasmodi‐ um falciparum* chloroqiune-resistance transporter (PfCRT) gene is responsible for chloro‐ qiune-resistant falciparum malaria [167] whereas diaappearance of the K76T mutation in PfCRT is associated with chloroquine susceptibility [168]. Oral artemisinin -based combina‐ tion therapies (artesunate + mefloquine, artesunate + sulfadoxine-pyrimethamine, artesunate + amodioquine, or artemether + lumefantrine) are the best antimalarial drugs [169, 170]. Ad‐ ditionally, the World Health Organization (WHO) recommends oral treatment of dihydroar‐ temisinin plus piperaquine as soon as the patients is able to take oral medication but not before a minimum of 24 hours of parenteral treatment [171]. The WHO recommended that intravenous artesunate can be used preferentially over quinine for the treatment of severe malaria caused by any *Plasmodium* species in both children and adults [172]. Oral artemisi‐ nin-based combination therapies have also demonstrated equivalent (if not better) efficacy in the treatment of uncomplicated malaria caused by all *Plasmodium* species and chloro‐ quine-resistant *Plasmodium vivax* in both children and adults [172]. Hence, conventional therapeutic regimens continue to be efficacious [172]. Insecticide-treated bed-nets in which insecticide is incorporated into the net fibers is evidenced to be the best way to prevent ma‐ laria [173]. It is demonstrated that RTS, S/ASO2, a vaccine has demonstrated promising re‐

Pulmonary amoebiasis that caused by the protozoan parasite, *Entamoeba histolytica* occurs mainly by the extension from the amoebic liver abscess [174, 175]. In a nine-year prospective study in a cohort of preschool children in Dhaka, Bangladesh demonstrated that a single amino acid polymorphism (Q223R) in the leptin receptor was associated with increased susceptibility to *Entamoeba histolytica* infection [176]. Children with two arginine alleles (223R) were nearly four times more likely to infect with *Entamoeba histolytica* as compared to those homozygous for glutamine (223Q) [176]. An *in vitro* study demonstrated that leptin signaling protected human epithelial cells from amoebic killing via a STAT3- dependent pathway [177]. It was identified that children who were heterozygous for the HLA class II *DQB1\*0601/DRB1\*1501* haplotype were more likely to *Entamoeba histolytica* negative [178]. The immune mechanism that explains why only a subset of *Entamoeba histolytica*-exposed persons develops clinical disease is not fully understood [179]. The effect of microbiota on immune response to *Entamoeba histolytica* and its virulence is not yet known [179]. The presence of cysts or trophozoites of amoeba in the stool does not imply that the disease is caused by *Entamoeba histolytica* as other two non-pathogenic species found in humans (*Entamoeba dispar* and *Entamoeba moshkovskii*) are morphologically indistinguishable, but can be rapidly, accurately, and effectively diagnosed by a single-round PCR [78, 180, 181]. Other diagnostic methods include culture of *Entamoeba histolytica*, ELISA, indirect fluorescent antibody test (IFAT), and indirect hemagglutination test (IHA) [78, 180, 181]. A combination of serological tests with identification of the parasite by PCR or antigen detection is the best diagnostic approach [182]. Active trophozoites of *Entamoeba histolytica* can be identified in sputum or pleural specimen [78]. Physical examina‐

sults in endemic areas [173].

338 HLA and Associated Important Diseases

**7. Pulmonary amoebiasis and HLA**

Pulmonary or visceral leishmaniasis, also called " Kala azar " is caused by *Leishmania donova‐ ni* and and *Leishmania chagasi* or *infantum* [186] is transmitted by various species of *Pheboto‐ mus*, a type of sand fly [187]. *Leishmania amastigotes* can be identified in pulmonary septa, alveoli, and the BAL fluid [188, 189]. Pleural effusion, mediastinal lymphadenopathy, and pneumonitis have been reported in HIV-infected patients with visceral leishmaniasis and lung transplant patients [188, 189]. The expansion of the HIV- infection/AIDS epidemic over leishmaniasis, particularly visceral leishmaniasis endemic regions has increased the number of co-infected patients [190] indicating that visceral leishmaniasis is an opportunistic disease in HIV-infected/AIDS patients although not yet considered an AIDS-defining disease [191]. According to sharing of immune-compromising mechanisms of both infections with *Leishma‐ nia infantum* and HIV-1 that may affect the parasite control in visceral leishmaniasis co-infected patients [191]. In comparison to patients with visceral leishmaniasis alone, co-infected patients present a more severe disease with increased parasite burden, frequent relapses, and anti‐ leishmanial drug resistance [190, 192]. On the other hand, Leishmania infection can impair both the chronic immune activation and the lymphocyte depletion and can accelerate pro‐ gression to AIDS, particularly in HIV-1-infected individuals [193, 194]. Hence, serological testings for latent infection due to *Leishmania* species are indicated in the pre-transplantation screening from endemic areas [195]. A recent study in two populations from Brazil (cases) and India (controls) demonstrated that the *HLA-DRB1-HLA-DQA1 HLA* class II region strongly contributed to visceral leishmaniasis susceptibility, indicating shared risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species [196]. Several previous studies of *Leishmania donovani* in mice model demonstrated dramatic differences in visceral disease in spleens and livers in congenic mice with different H-2 haplotypes [197]. There was evidenced that noncuring and curing responses mapped to the HLA-class II molecules by using recombinant congenic mice [198] and functional analysis blocking IA or IE (corresponding to DQ and DR, respectively) molecules *in vivo* with mono‐ clonal antibodies [199]. A significant role for CD8+ T-cells has also been shown in *Leishmania donovani* [200, 201]. A previous case-control study in Tunisia demonstrated that visceral leishmaniasis was associated with *DR/DQ* class II genes but not with *TNF/LTA* or *HSP70* class III loci [202]. Associations between delayed-type hypersensitivity-positive asymptomatic persons and *TNF* alleles were identified [203]. Positive associations between polymorphisms and various clinical phenotypes for cutaneous leishmaniasis have been demonstrated in a number of small case-control studies [204]. A recent study demonstrated a trend towards susceptibility to cutaneous leishmaniasis for alleles *HLA-DRB1\*13*, *HLA- B\*35*, and *HLA-B\*44* [205]. *HLA-B\*49* allele tended towards susceptibility to recurrent American cutaneous leishmaniasis (ACL), and *HLA-B\*52* to re-infection whereas presence of *HLA-B\*45* tended towards protection of against the cutaneous form of ACL [205]. *A\*02B\*44 DRB1\*07* and *A\*24B\*35 DRB1\*01* alleles, the most frequent haplotypes may be associated with susceptibility to ACL [205]. Immune activation can profoundly impact the visceral lieshmaniasis clinical course and prognosis, leading to increase the risk of death even under treatment of leishma‐ niasis [206]. Pentavalent antimonials, pentamidine, and amphotericin B, particularly the liposome formulations, and miltefosine are the drugs for the treatment of lieshmaniasis [207]. A previous study demonstrated that Poly/hsp/pcDNA vaccine can significantly decrease parasite load in spleen and liver indicating a feasible, effective, and practical approach for visceral leishmaniasis [208].

highly polymorphic HLA class I (A, B, and C) and II (DR, DQ, and DP) molecules determine

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

tively [215]. A previous study in Mexican population demonstrated that *HLA –B\*39* and *HLA-DR4* alleles were associated with *Trypanosoma cruzi* infection while *HLA-A\*68* and *HLA-DR16* allele were markers of protection of development of chronic Chagas' cardiomyopathy (CCC) and heart damage susceptibility, respectively [216]. Another study in Mexico revealed that *HLA-B\*39* and *HLA-DR\*4* alleles were also more frequently identified in patients with Chagas' disease [1]. A previous study in south-eastern Brazil demonstrated that *HLA-A\*30* and *HLA-DQB1\*06* alleles were associated with susceptibility to Chagas' disease and protec‐ tion of Chagas' disease, respectively in regardless of the clinical form of the disease, respec‐ tively [217] while *HLA-DR2* allele was associated with susceptibility to chronic Chagas' disease [218]. Nevertheless, in another previous study revealed that polymorphism of *HLA-DR* and *HLA-DQ* alleles did not influence on the susceptibility to different clinical forms of Chagas' disease or the progression to severe Chagas' cardiomyopathy [219]. A study in Chile, it was found that *HLA-B\*40* antigen in the presence of Cw3 was significantly lower in patients with CCC [220] and was higher expressed in subjects without cardiac disease in the city of Santiago [221]. A previous study in Venezuela in comparison of HLA class II allele frequencies between patients with Chagas' disease and controls demonstrated a higher frequency of *DQB1\*0501*, *DRB1\*01*, and *DRB1\*08* alleles, and a decreased frequency of *DQB1\*0303* and *DRB1\*14* alleles whereas patients with congestive heart failure and arrhythmia revealed decreased frequency of *DRB1\*1501* allele [222]. A higher frequency of the *HLA-DPB1\*0401* allele and *DPB1\*0401- HLA-DPB1\*2301* or *DPB1\*0401-DPB1\*3901* haplotype was identified in patients with cardiac manifestations in an endemic area of central Venezuela [223] whereas susceptibility between *HLA-C\*03* allele and CCC was confirmed [224]. In several Latin American mestizos from different countries and patients with CCC, there was an increase frequency of *HLA-A\*31*, *- B\*39*, and *-DR8* alleles and a decrease of frequency of *HLA-DQ1*, -*DQ3*, -*DR4*, and -*DR5* alleles [225]. A study in Bolivia revealed that *HLA-DRB1\*0102*, - *DRB\*1402*, and *MICA\*011* alleles were in strong linkage disequilibrium and there was association between the *HLA-DRB1\*01- B\*14-MICA\*011* haplotype and the resistance against chronic Chagas' disease whereas the frequencies of *HLA-DRB1\*01* and *HLA- B\*1402* alleles were significant lower in patients with electrocardiogram alteration and/or megacolon compared with a group of patients with indeterminate clinical form [226]. In a study in Argentine population, the class II alleles *HLA-DRB1\*0409* and *HLA-DRB1\*1503* were significantly more prevalent in Chagas' disease and *HLA-DRB1\*1103* allele was associated with Chagas' disease resistance whereas increased frequency of *DRB1\*1503* allele was identified in patients with CCC [227, 228]. A previous study on treatment of relapsing trypanosomiasis in Gambian population demonstrated that a 7-day course of intravenous eflornithine was satisfactory and would result in substantial savings compared with the standard 14-day regimen although the prior regimen was inferior to the standard regimen and could be used by the national control programmes in endemic areas, provided that its efficacy was closely monitored whereas melarsoprol remains the only effectively therapeutic option for new cases [229]. In animal experimental studies, eflornithine and melasoprol synergistically act against trypanosomes since the former drug decreases the trypanothione production, the target of the latter drug [230, 231]. A recent study demonstrated

and CD4+

T-cells, respec‐

341

http://dx.doi.org/10.5772/58288

the efficiency of presentation of *Trypanosoma cruzi* epitopes to CD8+

### **9. Pulmonary trypanosomiasis and HLA**

Human African trypanosomiasis (HAT) or sleeping sickness is caused by an extracellularly protozoan parasite, called " *Trypanosoma brucei gambiense* " [209], "*Trypanosoma brucei rhode‐ siense* " [210] and " *Trypanosoma cruzi* " which was discovered by Carlos Chagas in 1909 [211] and endemic to West Africa and Central Africa, mostly in Democratic Republic of Congo, Angola, Chad, Central African Republic, Uganda, and Sudan [209]. HAT continues to threat more than 60 million people in 36 sub-Saharan countries [209, 212]. In mice model, hypercel‐ lularity and edema of alveolar walls, approximately 10 times thicker than normal alveolar wall are identified and results in wall thickening although parasites are not demonstrated in alveoli [211]. Thickening and edema of bronchial walls of small and medium size bronchi due to parasite infiltration and significant inflammatory reaction (except large bronchi) in mice model were observed [211]. These bronchial inflammatory changes result in bronchial lumen reduction [211]. Most infected mice demonstrated infiltration of the walls of large blood vessels with extensive clusters of parasites in the myocytes of the muscular stratum and accompanying by an inflammatory reaction, interstitial edema, and rupture of muscle fibers [211]. These pathologically lung changes can contribute to pulmonary alveolar hemorrhage, bronchiolitis, and pneumonitis [211]. Pulmonary emphysema was also observed in the lungs of infected rats [213]. By the statistical analysis, the difference between experimental groups in lung-parasitic distribution and the degree of inflammatory reaction demonstrated no statistical difference [211]. Most Mexican strains demonstrated cardiomyotropism [211] and could cause pulmo‐ nary hypertension that could result in a dilatation of the right ventricle which is a typical characteristic of Chagas' disease caused by *Trypanosoma cruzi* without affecting the left ventricle [211]. However, many cases of Chagas' disease with pulmonary hypertension associated with right ventricular dilatation could attribute to left ventricular failure [214]. Several HLA alleles and haplotype associated with Chagas' disease have studied [215]. The persons and *TNF* alleles were identified [203]. Positive associations between polymorphisms and various clinical phenotypes for cutaneous leishmaniasis have been demonstrated in a number of small case-control studies [204]. A recent study demonstrated a trend towards susceptibility to cutaneous leishmaniasis for alleles *HLA-DRB1\*13*, *HLA- B\*35*, and *HLA-B\*44* [205]. *HLA-B\*49* allele tended towards susceptibility to recurrent American cutaneous leishmaniasis (ACL), and *HLA-B\*52* to re-infection whereas presence of *HLA-B\*45* tended towards protection of against the cutaneous form of ACL [205]. *A\*02B\*44 DRB1\*07* and *A\*24B\*35 DRB1\*01* alleles, the most frequent haplotypes may be associated with susceptibility to ACL [205]. Immune activation can profoundly impact the visceral lieshmaniasis clinical course and prognosis, leading to increase the risk of death even under treatment of leishma‐ niasis [206]. Pentavalent antimonials, pentamidine, and amphotericin B, particularly the liposome formulations, and miltefosine are the drugs for the treatment of lieshmaniasis [207]. A previous study demonstrated that Poly/hsp/pcDNA vaccine can significantly decrease parasite load in spleen and liver indicating a feasible, effective, and practical approach for

Human African trypanosomiasis (HAT) or sleeping sickness is caused by an extracellularly protozoan parasite, called " *Trypanosoma brucei gambiense* " [209], "*Trypanosoma brucei rhode‐ siense* " [210] and " *Trypanosoma cruzi* " which was discovered by Carlos Chagas in 1909 [211] and endemic to West Africa and Central Africa, mostly in Democratic Republic of Congo, Angola, Chad, Central African Republic, Uganda, and Sudan [209]. HAT continues to threat more than 60 million people in 36 sub-Saharan countries [209, 212]. In mice model, hypercel‐ lularity and edema of alveolar walls, approximately 10 times thicker than normal alveolar wall are identified and results in wall thickening although parasites are not demonstrated in alveoli [211]. Thickening and edema of bronchial walls of small and medium size bronchi due to parasite infiltration and significant inflammatory reaction (except large bronchi) in mice model were observed [211]. These bronchial inflammatory changes result in bronchial lumen reduction [211]. Most infected mice demonstrated infiltration of the walls of large blood vessels with extensive clusters of parasites in the myocytes of the muscular stratum and accompanying by an inflammatory reaction, interstitial edema, and rupture of muscle fibers [211]. These pathologically lung changes can contribute to pulmonary alveolar hemorrhage, bronchiolitis, and pneumonitis [211]. Pulmonary emphysema was also observed in the lungs of infected rats [213]. By the statistical analysis, the difference between experimental groups in lung-parasitic distribution and the degree of inflammatory reaction demonstrated no statistical difference [211]. Most Mexican strains demonstrated cardiomyotropism [211] and could cause pulmo‐ nary hypertension that could result in a dilatation of the right ventricle which is a typical characteristic of Chagas' disease caused by *Trypanosoma cruzi* without affecting the left ventricle [211]. However, many cases of Chagas' disease with pulmonary hypertension associated with right ventricular dilatation could attribute to left ventricular failure [214]. Several HLA alleles and haplotype associated with Chagas' disease have studied [215]. The

visceral leishmaniasis [208].

340 HLA and Associated Important Diseases

**9. Pulmonary trypanosomiasis and HLA**

highly polymorphic HLA class I (A, B, and C) and II (DR, DQ, and DP) molecules determine the efficiency of presentation of *Trypanosoma cruzi* epitopes to CD8+ and CD4+ T-cells, respec‐ tively [215]. A previous study in Mexican population demonstrated that *HLA –B\*39* and *HLA-DR4* alleles were associated with *Trypanosoma cruzi* infection while *HLA-A\*68* and *HLA-DR16* allele were markers of protection of development of chronic Chagas' cardiomyopathy (CCC) and heart damage susceptibility, respectively [216]. Another study in Mexico revealed that *HLA-B\*39* and *HLA-DR\*4* alleles were also more frequently identified in patients with Chagas' disease [1]. A previous study in south-eastern Brazil demonstrated that *HLA-A\*30* and *HLA-DQB1\*06* alleles were associated with susceptibility to Chagas' disease and protec‐ tion of Chagas' disease, respectively in regardless of the clinical form of the disease, respec‐ tively [217] while *HLA-DR2* allele was associated with susceptibility to chronic Chagas' disease [218]. Nevertheless, in another previous study revealed that polymorphism of *HLA-DR* and *HLA-DQ* alleles did not influence on the susceptibility to different clinical forms of Chagas' disease or the progression to severe Chagas' cardiomyopathy [219]. A study in Chile, it was found that *HLA-B\*40* antigen in the presence of Cw3 was significantly lower in patients with CCC [220] and was higher expressed in subjects without cardiac disease in the city of Santiago [221]. A previous study in Venezuela in comparison of HLA class II allele frequencies between patients with Chagas' disease and controls demonstrated a higher frequency of *DQB1\*0501*, *DRB1\*01*, and *DRB1\*08* alleles, and a decreased frequency of *DQB1\*0303* and *DRB1\*14* alleles whereas patients with congestive heart failure and arrhythmia revealed decreased frequency of *DRB1\*1501* allele [222]. A higher frequency of the *HLA-DPB1\*0401* allele and *DPB1\*0401- HLA-DPB1\*2301* or *DPB1\*0401-DPB1\*3901* haplotype was identified in patients with cardiac manifestations in an endemic area of central Venezuela [223] whereas susceptibility between *HLA-C\*03* allele and CCC was confirmed [224]. In several Latin American mestizos from different countries and patients with CCC, there was an increase frequency of *HLA-A\*31*, *- B\*39*, and *-DR8* alleles and a decrease of frequency of *HLA-DQ1*, -*DQ3*, -*DR4*, and -*DR5* alleles [225]. A study in Bolivia revealed that *HLA-DRB1\*0102*, - *DRB\*1402*, and *MICA\*011* alleles were in strong linkage disequilibrium and there was association between the *HLA-DRB1\*01- B\*14-MICA\*011* haplotype and the resistance against chronic Chagas' disease whereas the frequencies of *HLA-DRB1\*01* and *HLA- B\*1402* alleles were significant lower in patients with electrocardiogram alteration and/or megacolon compared with a group of patients with indeterminate clinical form [226]. In a study in Argentine population, the class II alleles *HLA-DRB1\*0409* and *HLA-DRB1\*1503* were significantly more prevalent in Chagas' disease and *HLA-DRB1\*1103* allele was associated with Chagas' disease resistance whereas increased frequency of *DRB1\*1503* allele was identified in patients with CCC [227, 228]. A previous study on treatment of relapsing trypanosomiasis in Gambian population demonstrated that a 7-day course of intravenous eflornithine was satisfactory and would result in substantial savings compared with the standard 14-day regimen although the prior regimen was inferior to the standard regimen and could be used by the national control programmes in endemic areas, provided that its efficacy was closely monitored whereas melarsoprol remains the only effectively therapeutic option for new cases [229]. In animal experimental studies, eflornithine and melasoprol synergistically act against trypanosomes since the former drug decreases the trypanothione production, the target of the latter drug [230, 231]. A recent study demonstrated that oxidative stress could contribute to parasite persistence in host tissue and the development of anti-*Trypanosoma cruzi* drugs [232].

**11. Pulmonary toxoplasmosis and HLA**

pyrimethamine and sulfadiazine [78].

**12. Pulmonary dengue viral infection and HLA**

This disease is caused by dengue virus (DENV) that belong to the family *Flaviviridae*, genus *Flavivirus*, and is transmitted to humans by *Aedes* mosquitoes, mainly *Aedes aegypti* [252]. Four serotypes of virus have been identified ; DENV-1, DENV-2, DENV-3, and DENV-4 [252]. An estimated 50 million-infected people occur each year and more than 2.5 billion people are being at risk of infection [253]. Epidemic with high incidences of dengue hemor‐ rhagic fever have been linked to primary infection with DENV-1 followed by infection with DENV-2 or DENV-3 whereas it indicated that the longer the interval between primary and secondary infections, the higher the risk of developing severe disease [254-256]. In adults, primary infections with each of four DENV serotypes, especially with DENV-1 and DENV-3, frequently results in dengue fever whereas some outbreak of primary infections with DENV-2 have been predominantly subclinical [257]. However, adult- dengue infec‐

A celled protozoan parasite, called " *Toxoplasma gondii* " which are primarily carried by cats is causal microorganism [245]. Humans are infected by ingestion of parasitic cyst- contami‐ nated uncooked milk product, vegetables or meat [78]. The clinical manifestations are influ‐ enza-liked illness, myalgia or enlarged lymph nodes [78] which is the most common recognized clinical manifestation [246]. Pulmonary involvement has been increasingly re‐ ported in HIV-infected/AIDS patients [78]. Pulmonary manifestations may be interstitial pneumonia, diffuse alveolar damage or necrotizing pneumonia [247]. Nevertheless, obstruc‐ tive or lobar pneumonia has been reported in a 49-year-old Spanish heterosexual man [246]. Early pregnancy with toxoplasmosis can cause fetal death, and chorioretinitis and neurolog‐ ical symptoms in the newborn whereas chronic disease can cause chorioretinitis, jaundice, convulsion, and encephalitis [78]. Association between the *HLA-DQ\*3* allele and the suscept‐ ibility to toxoplasmic encephalitis in HIV-infected/AIDS patients has been reported [248]. A previous study among Caucasians demonstrated that the *DQ3* gene frequency was signifi‐ cantly higher in infected infants with hydrocephalus than subjects without hydrocephalus [249]. In infected- mice model, human major histocompatibility MHC-class II transgenes re‐ duced parasite burden and brain necrosis that was consistent with the observed association between *HLA-DQ\*3* allele and hydrocephalus in human infants [249]. In the murine model, the *DQ3* (*DQ8*, *DQB1\*0302*) gene protected less than *DQ1* (*DQ6*, *DQB1\*0601*) [249]. These significant findings can provide characterization of the human immune responses that are pathogenic or protective in *Toxoplasma gondii* infections. Diagnosis of toxoplasmosis is based on detection of the protozoan parasites in the body tissues [78]. Sputum examination was used in diagnosis of pulmonary or disseminated toxoplasmosis in a 14-year-old allogeneic bone marrow recipient with graft- versus-host disease by identification of *Toxoplasma gondii* tachyzoites in sputum smears [250]. Serodiagnosis is unable to discriminate between active and chronic *Toxoplasma gondii* infection due to ability to increase the antibody levels without active disease [78]. A real-time-PCR-based assay in BAL fluid has been performed in HIVinfected/AIDS patients [251]. Toxoplasmosis can be treated with a combination regimen of

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

343

### **10. Pulmonary larval migrans**

*Toxocara* larval migrans caused by *Toxocara canis*, a parasite in dogs' intestine and *Toxocara catis*, a parasite in cats' intestine infected intermediate host, humans by ingestion these em‐ bryonated *Toxocara* eggs which hatch into infective larvae in the human intestine [78]. The infective larvae then penetrate the intestinal wall and are carried by blood circulation to many organs including lungs, liver, central nervous system, eyes, and muscles [78]. Granu‐ lomata then occur in these organs and later develop fibrosis and calcification [78]. A previ‐ ous study indicated that *Toxocara* species infections were associated with a polarized CD4 Th2-dominat immunity and eosinophilia, mediated mainly be HLA class II molecules, and Foxp3+ CD4+ CD25+ -expressing T regulatory (Treg) cells play a role in regulation of the im‐ munopathology of *Toxocara* granulomas in experimental animals and in enhancing the ex‐ pression of TGF-β1, which is an important function of Treg demonstrated during *Toxocara canis* invasion in the mouse' s brain [233]. The potential susceptibility loci HLA class II mole‐ cules are considered to be involved in regulation of a Th2-dominant immunity which is highly controlled by stimulation through TGF-β1 [233]. Exploration of TGF-β1 polymor‐ phism, Fox3+ CD4+ CD25+ Treg cells permit insight into the contribution produced by envi‐ ronmental and genetic factors in influencing disease syndrome type and severity in human toxocariasis [233]. Pulmonary manifestations are found in 80% and present with severe asth‐ ma [78]. Clinical manifestations may demonstrate scattered rales and rhonchi on ausculta‐ tion including fever, cough, hepatosplenomegaly, generalized lymph node enlargement, eye pain, strabismus, white pupil, unilaterally visual loss, abdominal pain, and neurological manifestations [78]. Some cases may present with severe eosinophilic pneumonia and may contribute to respiratory distress syndrome [234-236]. Chest roentgenogram may demon‐ strate localized patchy infiltrates [78]. This syndrome is usually associated with eosinophilia, elevated antibody titers to *Toxocara canis*, and increased total serum IgE level [237, 238]. About 25% of childhood patients have no eosinophilia [239]. Identification of serum IgE an‐ tibodies by ELISA [240] and *Toxocara* excretory-secretory antigens by Western-blotting method have been reported for diagnosis [241]. Nevertheless, serodiagnostic methods can‐ not distinguish between past and current infections [240, 241]. *Toxocara* eggs or larvae can‐ not be identified in the feces since human is not the definitive host [78]. Histopathological examination of lung or liver biopsy specimens may reveal granulomas with multinucleated giant cells, eosinophils, and fibrosis [78]. *Toxocara* larval migrans may be spontaneous reso‐ lution, therefore, mild to moderate symptomatic patients need not any treatment [78]. How‐ ever, patients with severe *Toxocara* larval migrans can be treated with diethylcarbamazine 6 mg/kg/day, 21 days) [242], mebendazole (20-25 mg/kg/day, 21 days) [243] or albendazole (10 mg/kg/day, 5 days) [244]. Exacerbation of the inflammatory reactions in the tissues due to killing of the larvae may occur, therefore, antihelminthics plus corticosteroids is recom‐ mended [78].

### **11. Pulmonary toxoplasmosis and HLA**

that oxidative stress could contribute to parasite persistence in host tissue and the development

*Toxocara* larval migrans caused by *Toxocara canis*, a parasite in dogs' intestine and *Toxocara catis*, a parasite in cats' intestine infected intermediate host, humans by ingestion these em‐ bryonated *Toxocara* eggs which hatch into infective larvae in the human intestine [78]. The infective larvae then penetrate the intestinal wall and are carried by blood circulation to many organs including lungs, liver, central nervous system, eyes, and muscles [78]. Granu‐ lomata then occur in these organs and later develop fibrosis and calcification [78]. A previ‐ ous study indicated that *Toxocara* species infections were associated with a polarized CD4 Th2-dominat immunity and eosinophilia, mediated mainly be HLA class II molecules, and

munopathology of *Toxocara* granulomas in experimental animals and in enhancing the ex‐ pression of TGF-β1, which is an important function of Treg demonstrated during *Toxocara canis* invasion in the mouse' s brain [233]. The potential susceptibility loci HLA class II mole‐ cules are considered to be involved in regulation of a Th2-dominant immunity which is highly controlled by stimulation through TGF-β1 [233]. Exploration of TGF-β1 polymor‐

ronmental and genetic factors in influencing disease syndrome type and severity in human toxocariasis [233]. Pulmonary manifestations are found in 80% and present with severe asth‐ ma [78]. Clinical manifestations may demonstrate scattered rales and rhonchi on ausculta‐ tion including fever, cough, hepatosplenomegaly, generalized lymph node enlargement, eye pain, strabismus, white pupil, unilaterally visual loss, abdominal pain, and neurological manifestations [78]. Some cases may present with severe eosinophilic pneumonia and may contribute to respiratory distress syndrome [234-236]. Chest roentgenogram may demon‐ strate localized patchy infiltrates [78]. This syndrome is usually associated with eosinophilia, elevated antibody titers to *Toxocara canis*, and increased total serum IgE level [237, 238]. About 25% of childhood patients have no eosinophilia [239]. Identification of serum IgE an‐ tibodies by ELISA [240] and *Toxocara* excretory-secretory antigens by Western-blotting method have been reported for diagnosis [241]. Nevertheless, serodiagnostic methods can‐ not distinguish between past and current infections [240, 241]. *Toxocara* eggs or larvae can‐ not be identified in the feces since human is not the definitive host [78]. Histopathological examination of lung or liver biopsy specimens may reveal granulomas with multinucleated giant cells, eosinophils, and fibrosis [78]. *Toxocara* larval migrans may be spontaneous reso‐ lution, therefore, mild to moderate symptomatic patients need not any treatment [78]. How‐ ever, patients with severe *Toxocara* larval migrans can be treated with diethylcarbamazine 6 mg/kg/day, 21 days) [242], mebendazole (20-25 mg/kg/day, 21 days) [243] or albendazole (10 mg/kg/day, 5 days) [244]. Exacerbation of the inflammatory reactions in the tissues due to killing of the larvae may occur, therefore, antihelminthics plus corticosteroids is recom‐


Treg cells permit insight into the contribution produced by envi‐

of anti-*Trypanosoma cruzi* drugs [232].

342 HLA and Associated Important Diseases

**10. Pulmonary larval migrans**

CD25+

CD25+

Foxp3+ CD4+

phism, Fox3+ CD4+

mended [78].

A celled protozoan parasite, called " *Toxoplasma gondii* " which are primarily carried by cats is causal microorganism [245]. Humans are infected by ingestion of parasitic cyst- contami‐ nated uncooked milk product, vegetables or meat [78]. The clinical manifestations are influ‐ enza-liked illness, myalgia or enlarged lymph nodes [78] which is the most common recognized clinical manifestation [246]. Pulmonary involvement has been increasingly re‐ ported in HIV-infected/AIDS patients [78]. Pulmonary manifestations may be interstitial pneumonia, diffuse alveolar damage or necrotizing pneumonia [247]. Nevertheless, obstruc‐ tive or lobar pneumonia has been reported in a 49-year-old Spanish heterosexual man [246]. Early pregnancy with toxoplasmosis can cause fetal death, and chorioretinitis and neurolog‐ ical symptoms in the newborn whereas chronic disease can cause chorioretinitis, jaundice, convulsion, and encephalitis [78]. Association between the *HLA-DQ\*3* allele and the suscept‐ ibility to toxoplasmic encephalitis in HIV-infected/AIDS patients has been reported [248]. A previous study among Caucasians demonstrated that the *DQ3* gene frequency was signifi‐ cantly higher in infected infants with hydrocephalus than subjects without hydrocephalus [249]. In infected- mice model, human major histocompatibility MHC-class II transgenes re‐ duced parasite burden and brain necrosis that was consistent with the observed association between *HLA-DQ\*3* allele and hydrocephalus in human infants [249]. In the murine model, the *DQ3* (*DQ8*, *DQB1\*0302*) gene protected less than *DQ1* (*DQ6*, *DQB1\*0601*) [249]. These significant findings can provide characterization of the human immune responses that are pathogenic or protective in *Toxoplasma gondii* infections. Diagnosis of toxoplasmosis is based on detection of the protozoan parasites in the body tissues [78]. Sputum examination was used in diagnosis of pulmonary or disseminated toxoplasmosis in a 14-year-old allogeneic bone marrow recipient with graft- versus-host disease by identification of *Toxoplasma gondii* tachyzoites in sputum smears [250]. Serodiagnosis is unable to discriminate between active and chronic *Toxoplasma gondii* infection due to ability to increase the antibody levels without active disease [78]. A real-time-PCR-based assay in BAL fluid has been performed in HIVinfected/AIDS patients [251]. Toxoplasmosis can be treated with a combination regimen of pyrimethamine and sulfadiazine [78].

### **12. Pulmonary dengue viral infection and HLA**

This disease is caused by dengue virus (DENV) that belong to the family *Flaviviridae*, genus *Flavivirus*, and is transmitted to humans by *Aedes* mosquitoes, mainly *Aedes aegypti* [252]. Four serotypes of virus have been identified ; DENV-1, DENV-2, DENV-3, and DENV-4 [252]. An estimated 50 million-infected people occur each year and more than 2.5 billion people are being at risk of infection [253]. Epidemic with high incidences of dengue hemor‐ rhagic fever have been linked to primary infection with DENV-1 followed by infection with DENV-2 or DENV-3 whereas it indicated that the longer the interval between primary and secondary infections, the higher the risk of developing severe disease [254-256]. In adults, primary infections with each of four DENV serotypes, especially with DENV-1 and DENV-3, frequently results in dengue fever whereas some outbreak of primary infections with DENV-2 have been predominantly subclinical [257]. However, adult- dengue infec‐ tions are frequently accompanied by a tendency for severe hemorrhage [258] and can be lifethreatening when infections occur in patients with chronic diseases such as asthma and diabetes [259-261]. Several HLA class I alleles, female sex, AB blood group, a single-nucleo‐ tide polymorphism in the tumor necrosis factor gene, and a promoter variant of the DC-SIGN receptor gene are the host factors that increase the risk of severe dengue disease [262-267]. Notably, the first outbreak in the Americas occurred in 1981, which coincided with the introduction of the possibly more virulent DENV-2 Southeast Asian genotype whereas the less virulent indigenous DENV-2 genotype was already circulating in the re‐ gion [259, 268-270]. Age has been demonstrated to influence the disease outcome following a secondary infection with heterologous DENV [271]. In Asia, the risk of severe disease is greater in children than in adults, in contrast to the Americas [272, 273]. Nevertheless, the finding that dengue hemorrhagic fever or dengue shock syndrome is noted primarily in a relative small percentage of secondary DENV infections and to a much lesser extent in pri‐ mary infections although with virulent strains indicates that host factors must be critical de‐ terminants of severe DENV disease development [252]. There is evidence that DENV antigen is present in the pulmonary vascular endothelium [274] whereas liver is the organ commonly involved in human DENV infections including mouse model [275, 276]. Glu‐ cose-6-phosphate dehydrogenase deficiency which is highly prevalence identified among African population [277] can cause abnormal cellular redox, therefore affecting production of hydrogen peroxide, superoxide, and nitric oxide indicating oxidative stress [278]. Viral proliferation and virulence by increasing viral receptors on target cells or increasing of viral particles is known to be affected by oxidative stress [278], therefore, glucose-6-phosphate de‐ hydrogenase deficiency may contribute to increased replication of DENV in monocytes [277]. Several human HLA class I alleles *(-A\*01*, *-A\*0207*, *-A\*24*, - *B\*07*, *-B\*46*, *-B\*51*) [262, 264, 279] and HLA class II alleles *(-DQ\*1*, *-DR\*1*, *-DR\*4*) [263, 280] are associated with devel‐ opment of dengue hemorrhagic fever. Additionally, a recent study demonstrated that signif‐ icantly higher frequency of *HLA-A\*33* allele in dengue fever patients, *HLA-A\*0211* allele in dengue hemorrhagic fever cases compared to controls and dengue fever cases, respectively [281]. The frequency of *HLA-B\*18* and *HLA-Cw\*07* alleles were significantly higher in DENV-infected cases compared to controls [281]. The combined frequency of *HLA-Cw\*07* with *HLA-DRB1\*07/\*15* genotype was significantly higher in dengue hemorrhagic fever cas‐ es as compared to dengue fever cases and controls but the frequency of combination of *HLA-Cw\*07* allele without *HLA-DRB1\*07* allele was significantly higher in dengue fever cas‐ es compared to controls [281]. This study results indicate that *HLA-A\*33* allele may be asso‐ ciated with development of dengue fever whereas *HLA-B\*18* and *HLA-Cw\*07* alleles may be associated with symptomatic dengue infection requiring hospitalization [281]. A previous study demonstrated that *HLA-A\*0207* and *HLA-B\*51* alleles was associated with dengue hemorrhagic fever in patients having secondary DENV-1 or DENV-2 infection only and chil‐ dren with *HLA-A\*24* allele were more likely to develop dengue hemorrhagic fever [282]. Af‐ ter secondary dengue infections, *HLA-B\*44*, *-B\*62*, *-B\*76*, and *-B\*77* alleles revealed to protect against development of clinical disease [282]. Clinical findings in early febrile stage include fever, headache, malaise, rash, body pain, and later develops pleural effusion [258, 283], both lower lobes infiltration [283], bilateral perihilar edema [284], ascites, bleeding, thrombocytopenia (platelet < 100,000 per mm3 ), hematocrit > 20%, and clinical warning signs such as restlessness, severe and continuous abdominal pain, persistent vomiting and a sud‐

den reduction in body temperature associated with profuse perspiration, adynamia (vigor or loss of strength) and sometimes fainting which can be indicative of shock due to plasma extravasation [258]. Dengue disease must be excluded from two syndromes related to hanta‐ virus, hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome (HPS) in Americas [285-287]. HPS is typically characterized by acute noncardio‐ genic pulmonary edema and circulatory shock whereas fever, hemorrhagia, and acute renal failure are hallmark findings in HFRS [288]. Laboratory diagnosis of DENV infection in‐ clude virus isolation, serodiagnostic tests (MAC-ELISA, IgG ELISA, IgG : IgM ratio, neutral‐ ization assay), nucleic acid-amplification tests (real-time PCR, reverse-transcriptase PCR, nucleic acid- sequence based amplification assay (NASBA)), and antigen detection (NS1 an‐ tigen and antibody detection) [258]. DENV complications include massive hemorrhage, dis‐ seminated intravascular coagulation, non-cardiogenic pulmonary edema, respiratory failure, and finally develops multiple organ failure [258]. In uncomplicated dengue cases, treatment is only supportive, but in cases with prolonged or recurrent dengue shock, intra‐ venous fluids should be administered carefully according to dosage and age to prevent pul‐ monary edema [258]. DENV control and prevention strategies include vector control and vaccine development [258]. Current approaches to vaccine development involve using deox‐ yribonucleic acid vaccine, chimeric viruses using yellow fever vaccine, subunit vaccine, in‐ activated viruses, attenuated viruses, and attenuated dengue viruses as backbones [289-294]. An Acambis/Sanofi Pasteur yellow fever-dengue chimeric vaccine is in advanced Phase II testing in children in Thailand [258]. A possible licensed vaccine will be available in less

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

345

Leptospirosis is a zoonotic disease caused by genus *Leptospira* which belongs to the phylum of spirochaetes [295]. The 8 pathogenic species of this genus are *Leptospira interrogans*, *Lepto‐ spira borgpetersenii*, *Leptospira noguchii*, *Leptospira santarosai*, *Leptospira kirschneri*, *Leptospira al‐ stonii*, *Leptospira alexanderi*, and *Leptospira weilii* [295]. Transmission of leptospirosis requires continuous enzoonotic circulation of the pathogen among animal reservoir or as commonly referred-maintenance host [295]. *Leptospira* serovars reveal specific host preferences with re‐ gard to their ability to produce high-grade carriage [295]. Rats (genus *Rattus*) serve as reser‐ voirs for the Icterohaemorrhagiae serogroup while house mice (*Mus musculus*) are the reservoir for the Ballum serogroup [295]. Additionally, serovars often do not cause signifi‐ cant disease in highly adapted-reservoir hosts [295]. A previous study demonstrated that *HLA-DQ\*6* allele increased risk of laboratory-confirmed leptospirosis [296]. Pathogenic spe‐ cies produce a systemic infection after an environmental exposure, establish persistent renal and urinary shedding in reservoir animals and cause tissue damage in multiple organs of susceptible hosts [295]. Humans are incidental hosts in which leptospirosis produces acute disease manifestations and does not induce a disease carrier state [295]. The incubation peri‐ od varies from 2 to 30 days [295]. Clinical presentation in human leptospirosis includes acute febrile illness that often cannot be differentiate from other causes of acute fever illness [295]. The clinical manifestations include fever, headache, myalgia (especially calf muscle), and prostration associated with any of the following symptoms or signs: cough, hemoptysis,

than 10 years [258].

**13. Pulmonary leptospirosis and HLA**

den reduction in body temperature associated with profuse perspiration, adynamia (vigor or loss of strength) and sometimes fainting which can be indicative of shock due to plasma extravasation [258]. Dengue disease must be excluded from two syndromes related to hanta‐ virus, hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome (HPS) in Americas [285-287]. HPS is typically characterized by acute noncardio‐ genic pulmonary edema and circulatory shock whereas fever, hemorrhagia, and acute renal failure are hallmark findings in HFRS [288]. Laboratory diagnosis of DENV infection in‐ clude virus isolation, serodiagnostic tests (MAC-ELISA, IgG ELISA, IgG : IgM ratio, neutral‐ ization assay), nucleic acid-amplification tests (real-time PCR, reverse-transcriptase PCR, nucleic acid- sequence based amplification assay (NASBA)), and antigen detection (NS1 an‐ tigen and antibody detection) [258]. DENV complications include massive hemorrhage, dis‐ seminated intravascular coagulation, non-cardiogenic pulmonary edema, respiratory failure, and finally develops multiple organ failure [258]. In uncomplicated dengue cases, treatment is only supportive, but in cases with prolonged or recurrent dengue shock, intra‐ venous fluids should be administered carefully according to dosage and age to prevent pul‐ monary edema [258]. DENV control and prevention strategies include vector control and vaccine development [258]. Current approaches to vaccine development involve using deox‐ yribonucleic acid vaccine, chimeric viruses using yellow fever vaccine, subunit vaccine, in‐ activated viruses, attenuated viruses, and attenuated dengue viruses as backbones [289-294]. An Acambis/Sanofi Pasteur yellow fever-dengue chimeric vaccine is in advanced Phase II testing in children in Thailand [258]. A possible licensed vaccine will be available in less than 10 years [258].

### **13. Pulmonary leptospirosis and HLA**

tions are frequently accompanied by a tendency for severe hemorrhage [258] and can be lifethreatening when infections occur in patients with chronic diseases such as asthma and diabetes [259-261]. Several HLA class I alleles, female sex, AB blood group, a single-nucleo‐ tide polymorphism in the tumor necrosis factor gene, and a promoter variant of the DC-SIGN receptor gene are the host factors that increase the risk of severe dengue disease [262-267]. Notably, the first outbreak in the Americas occurred in 1981, which coincided with the introduction of the possibly more virulent DENV-2 Southeast Asian genotype whereas the less virulent indigenous DENV-2 genotype was already circulating in the re‐ gion [259, 268-270]. Age has been demonstrated to influence the disease outcome following a secondary infection with heterologous DENV [271]. In Asia, the risk of severe disease is greater in children than in adults, in contrast to the Americas [272, 273]. Nevertheless, the finding that dengue hemorrhagic fever or dengue shock syndrome is noted primarily in a relative small percentage of secondary DENV infections and to a much lesser extent in pri‐ mary infections although with virulent strains indicates that host factors must be critical de‐ terminants of severe DENV disease development [252]. There is evidence that DENV antigen is present in the pulmonary vascular endothelium [274] whereas liver is the organ commonly involved in human DENV infections including mouse model [275, 276]. Glu‐ cose-6-phosphate dehydrogenase deficiency which is highly prevalence identified among African population [277] can cause abnormal cellular redox, therefore affecting production of hydrogen peroxide, superoxide, and nitric oxide indicating oxidative stress [278]. Viral proliferation and virulence by increasing viral receptors on target cells or increasing of viral particles is known to be affected by oxidative stress [278], therefore, glucose-6-phosphate de‐ hydrogenase deficiency may contribute to increased replication of DENV in monocytes [277]. Several human HLA class I alleles *(-A\*01*, *-A\*0207*, *-A\*24*, - *B\*07*, *-B\*46*, *-B\*51*) [262, 264, 279] and HLA class II alleles *(-DQ\*1*, *-DR\*1*, *-DR\*4*) [263, 280] are associated with devel‐ opment of dengue hemorrhagic fever. Additionally, a recent study demonstrated that signif‐ icantly higher frequency of *HLA-A\*33* allele in dengue fever patients, *HLA-A\*0211* allele in dengue hemorrhagic fever cases compared to controls and dengue fever cases, respectively [281]. The frequency of *HLA-B\*18* and *HLA-Cw\*07* alleles were significantly higher in DENV-infected cases compared to controls [281]. The combined frequency of *HLA-Cw\*07* with *HLA-DRB1\*07/\*15* genotype was significantly higher in dengue hemorrhagic fever cas‐ es as compared to dengue fever cases and controls but the frequency of combination of *HLA-Cw\*07* allele without *HLA-DRB1\*07* allele was significantly higher in dengue fever cas‐ es compared to controls [281]. This study results indicate that *HLA-A\*33* allele may be asso‐ ciated with development of dengue fever whereas *HLA-B\*18* and *HLA-Cw\*07* alleles may be associated with symptomatic dengue infection requiring hospitalization [281]. A previous study demonstrated that *HLA-A\*0207* and *HLA-B\*51* alleles was associated with dengue hemorrhagic fever in patients having secondary DENV-1 or DENV-2 infection only and chil‐ dren with *HLA-A\*24* allele were more likely to develop dengue hemorrhagic fever [282]. Af‐ ter secondary dengue infections, *HLA-B\*44*, *-B\*62*, *-B\*76*, and *-B\*77* alleles revealed to protect against development of clinical disease [282]. Clinical findings in early febrile stage include fever, headache, malaise, rash, body pain, and later develops pleural effusion [258, 283], both lower lobes infiltration [283], bilateral perihilar edema [284], ascites, bleeding,

344 HLA and Associated Important Diseases

thrombocytopenia (platelet < 100,000 per mm3

), hematocrit > 20%, and clinical warning signs

such as restlessness, severe and continuous abdominal pain, persistent vomiting and a sud‐

Leptospirosis is a zoonotic disease caused by genus *Leptospira* which belongs to the phylum of spirochaetes [295]. The 8 pathogenic species of this genus are *Leptospira interrogans*, *Lepto‐ spira borgpetersenii*, *Leptospira noguchii*, *Leptospira santarosai*, *Leptospira kirschneri*, *Leptospira al‐ stonii*, *Leptospira alexanderi*, and *Leptospira weilii* [295]. Transmission of leptospirosis requires continuous enzoonotic circulation of the pathogen among animal reservoir or as commonly referred-maintenance host [295]. *Leptospira* serovars reveal specific host preferences with re‐ gard to their ability to produce high-grade carriage [295]. Rats (genus *Rattus*) serve as reser‐ voirs for the Icterohaemorrhagiae serogroup while house mice (*Mus musculus*) are the reservoir for the Ballum serogroup [295]. Additionally, serovars often do not cause signifi‐ cant disease in highly adapted-reservoir hosts [295]. A previous study demonstrated that *HLA-DQ\*6* allele increased risk of laboratory-confirmed leptospirosis [296]. Pathogenic spe‐ cies produce a systemic infection after an environmental exposure, establish persistent renal and urinary shedding in reservoir animals and cause tissue damage in multiple organs of susceptible hosts [295]. Humans are incidental hosts in which leptospirosis produces acute disease manifestations and does not induce a disease carrier state [295]. The incubation peri‐ od varies from 2 to 30 days [295]. Clinical presentation in human leptospirosis includes acute febrile illness that often cannot be differentiate from other causes of acute fever illness [295]. The clinical manifestations include fever, headache, myalgia (especially calf muscle), and prostration associated with any of the following symptoms or signs: cough, hemoptysis, breathlessness, conjunctival suffusion, jaundice, oliguria or anuria, internal organ hemor‐ rhages, skin rash, cardiac arrhythmia or failure, and meningeal irritation [297]. Leptospiro‐ sis-associated pulmonary hemorrhage syndrome was first described in China and Korea and then was brought to global attention by a large outbreak of severe-from disease in Ni‐ caragua in 1995 [295]. The risks of developing severe leptospirosis include a critical thresh‐ old of qPCR- determined leptospiremia, identification of the infective strain, and early laboratory results [298]. The illness usually resolves after the first week of symptoms [295]. The presumptive diagnosis was made from a positive result of a rapid screening test such as latex agglutination test, IgM ELISA, dipstick, lateral flow, etc [297]. The confirmatory diag‐ nosis includes isolation of the organism from blood or other clinical specimens, a positive PCR result, and fourfold or greater rise in titer or seroconversion in microscopic agglutina‐ tion test (MAT) on paired samples obtained at least 2 weeks apart [297]. Severe case usually treated with intravenous benzylpenicillin (30 mg/kg up to 1.2 g intravenously and 6-hourly for 5-7 days) [297]. Oral administration of doxycycline (2 mg/kg up to 100 mg, 12-hourly for 5-7 days), amoxicillin, ampicillin, or tetracycline is the treatment of choice in less severe cas‐ es [297]. The third-generation cephalosporins, such as ceftriazone and cefotaxime, quinolone antimicrobials may also be effective, but Jarrisch-Herxheimer reactions can occur after the start of antimicrobial treatment [297]. The patients should be appropriate monitored and care supported, such as mechanical ventilation, dialysis, etc [297]. A recent study in Thai‐ land demonstrated that only the latex test could be considered cost-effective when com‐ pared to the no-antimicrobial option, and that latex test, microcapsule agglutination test, and lateral flow were still inferior to empirical treatment (7-day course of doxycycline, 100 mg bid treatment) [299]. A recent study on vaccine candidates for protection of leptospirosis successfully demonstrated LBJ\_2271 as a protein candidate for further study of antigenic im‐ mune stimulation for vaccine development [300] whereas another recent study revealed that czcA and its four subunit vaccine peptides could be ideal T-cell driven efficacious vaccine against this disease [301]. Until epidemiologically-validated immune correlates are deter‐ mined and discovery of vaccine candidates will likely continue to rely on the search for new virulence factors and outer membrane proteins of the organism.

**Disease Known HLA Influence Reference**

*Fg12(+158T/\*)* Susceptible 10

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

*HLA-DQB1\*0402* Decreased frequency 28

more poorer outcome

http://dx.doi.org/10.5772/58288

Relapse <sup>30</sup>

Protective

Susceptible

nervous system impairment

disease progression

both disease progression and central nervous system impairment

disease

form

chronically

Protective

or pulmonary leishmaniasis

Susceptible to cutaneous leishmaniasis

obstructive lymphatic

7, 8

347

10

26, 27, 28, 29

33

33

33

39

146

161, 163

196

205

SARS *HLA-B\*0703, HLADRB1\*0301* More prevalent and

*CXCL10(-938AA)/Fg12(+158T/\*)* or *CXCL10(-938AA)/*

*DRB1\*0803, HLA-DQA1\*0101, HLA-DQB1\*0501HLA-DRB1\*1501, HLA-DQB1\*0502, HLA-DQB1\*0503*

HLA-B\*17-tumor-necrosis-factor-α-238/A, HLA-tumornecrosis-factor-α-308/2, HLA-tumor-necrosis-factor-β-2

HIV-Infection/AIDS *HLA-B\*27, HLA-B\*57* Slow progression 33

*HLA-A\*24* More rapid central

*HLA-Cw\*2* Protective against

*HLA-DQB1\*2* Protective against

*HLA-A\*31, HLA-B\*41, HLA-DQB1\*5, HLA-DRB1\*10* Susceptible to TB

Malaria *HLA-B\*46, HLA-B\*56, HLA-DRB1\*1001, HLA-B\** Susceptible 160, 162

Amoebiasis *HLA-DQB1\*0601/DRB1\*1501* Protective 178

*KIR2DL3-HLA-C1, HLA-Bw\*53, HLA-DRB1\*1302, HLA-*

Leishmaniasis *HLA-DRB1, HLA-DQA1* Susceptible to visceral

*HLA-DRB1\*13, HLA-B\*35, HLA-B\*44, HLA-A\*02, HLA-B\*44, HLA-DRB1\*07, HLA-A\*24, HLA-DRB1\*01*

*DQB1\*0501*

*HLA-B\*15* Susceptible 148

Filariasis *CD8+ HLA-DR+* Susceptible to

*HO-1(-497A/\*)*

Tuberculosis *HLA-DQB1\*0601, HLA-DRB1\*1501HLA-DPB1\*02, HLA-*

### **14. Conclusions**

Most of several studies have inconclusively demonstrated statistical association between HLA class I and II molecules and susceptibility to a range of complex tropical pulmonary infectious diseases, particularly parasitic pulmonary diseases. The globalization of neglected tropical pulmonary infectious diseases can alert the healthcare providers in diagnosis in recent immigrants or travelers from endemic areas who present with respiratory manifestations and peripheral blood or tissue eosinophilia. A complete re-evaluation of the true impact of HLA/MHC genes on susceptibility to tropical pulmonary infectious diseases. Summary of association between known HLA alleles and susceptibility of some tropical pulmonary infectious diseases are shown in Table 1.

breathlessness, conjunctival suffusion, jaundice, oliguria or anuria, internal organ hemor‐ rhages, skin rash, cardiac arrhythmia or failure, and meningeal irritation [297]. Leptospiro‐ sis-associated pulmonary hemorrhage syndrome was first described in China and Korea and then was brought to global attention by a large outbreak of severe-from disease in Ni‐ caragua in 1995 [295]. The risks of developing severe leptospirosis include a critical thresh‐ old of qPCR- determined leptospiremia, identification of the infective strain, and early laboratory results [298]. The illness usually resolves after the first week of symptoms [295]. The presumptive diagnosis was made from a positive result of a rapid screening test such as latex agglutination test, IgM ELISA, dipstick, lateral flow, etc [297]. The confirmatory diag‐ nosis includes isolation of the organism from blood or other clinical specimens, a positive PCR result, and fourfold or greater rise in titer or seroconversion in microscopic agglutina‐ tion test (MAT) on paired samples obtained at least 2 weeks apart [297]. Severe case usually treated with intravenous benzylpenicillin (30 mg/kg up to 1.2 g intravenously and 6-hourly for 5-7 days) [297]. Oral administration of doxycycline (2 mg/kg up to 100 mg, 12-hourly for 5-7 days), amoxicillin, ampicillin, or tetracycline is the treatment of choice in less severe cas‐ es [297]. The third-generation cephalosporins, such as ceftriazone and cefotaxime, quinolone antimicrobials may also be effective, but Jarrisch-Herxheimer reactions can occur after the start of antimicrobial treatment [297]. The patients should be appropriate monitored and care supported, such as mechanical ventilation, dialysis, etc [297]. A recent study in Thai‐ land demonstrated that only the latex test could be considered cost-effective when com‐ pared to the no-antimicrobial option, and that latex test, microcapsule agglutination test, and lateral flow were still inferior to empirical treatment (7-day course of doxycycline, 100 mg bid treatment) [299]. A recent study on vaccine candidates for protection of leptospirosis successfully demonstrated LBJ\_2271 as a protein candidate for further study of antigenic im‐ mune stimulation for vaccine development [300] whereas another recent study revealed that czcA and its four subunit vaccine peptides could be ideal T-cell driven efficacious vaccine against this disease [301]. Until epidemiologically-validated immune correlates are deter‐ mined and discovery of vaccine candidates will likely continue to rely on the search for new

virulence factors and outer membrane proteins of the organism.

Most of several studies have inconclusively demonstrated statistical association between HLA class I and II molecules and susceptibility to a range of complex tropical pulmonary infectious diseases, particularly parasitic pulmonary diseases. The globalization of neglected tropical pulmonary infectious diseases can alert the healthcare providers in diagnosis in recent immigrants or travelers from endemic areas who present with respiratory manifestations and peripheral blood or tissue eosinophilia. A complete re-evaluation of the true impact of HLA/MHC genes on susceptibility to tropical pulmonary infectious diseases. Summary of association between known HLA alleles and susceptibility of some tropical pulmonary

**14. Conclusions**

346 HLA and Associated Important Diseases

infectious diseases are shown in Table 1.



**Author details**

Attapon Cheepsattayakorn1,2

Public Health, Thailand

**References**

42-49.

1999 ; 55 (2) : 401-413 C.

2005 ; 11 (8) : 875-879.

10.1186/1471-5-26

et 2003 Sep 12 ; 4(NA) : 9.

Address all correspondence to: attaponche@yahoo.com

1 10th Zonal Tuberculosis and Chest Disease Centre, Chiang Mai, Thailand

2 10th Office of Disease Prevention and Control, Department of Disease Control, Ministry of

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

349

[1] Alves C, Souza T, Meyer I. Immunogenetics and infectious diseases : special refer‐ ence to the major histocompatibility complex. Bra J Infect Dis 2006 ; 10 (2) : 122-131.

[2] Singh N, Agrawal S, Rastogi AK. Infectious diseases and immunity : special refer‐ ence response to major histocompatibility complex. Emerg Infect Dis 1997 ; 3 (1) :

[3] Hill AVS. Genetics and genomics of infectious disease susceptibility. Br Med Bull

[4] Itoyama S, Keicho N, Quy T, Phi NC, Long HT, Ha le D, *et al*. ACE1 polymorphism and progression of SARS. Biochem Biophys Res Commun 2004 ; 323 (3) : 1124-1129.

[5] Kuba K, Imai Y, Rao S, Huan Y, Guo F, Guan B, *et al*. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med

[6] Chan KCA, Tang NLS, Hui DSC, Chung GTY, Wu AKL, Chim SSC, *et al*. Absence of association between angiotensin converting enzyme polymorphism and develop‐ ment of adult respiratory distress syndrome in patients with severe acute respiratory syndrome : a case control study. BMC Infect Dis 2005 ; 5(NA) : 26. DOI :

[7] Ng MH, Lau KM, Li L, Cheng SH, Chan WY, Hui PK, *et al*. Association of humanleukocyte-antigen class I (B\*0703) and class II (DRB1\*0301) genotypes with suscepti‐ bility and resistance to the development of severe acute respiratory syndrome. J

[8] Lin M, Tseng HK, Trejaut JA, Lee HL, Loo JH, Chu CC, *et al*. Association of HLA class I with severe acute respiratory syndrome coronavirus infection. BMC Med Gen‐

Infect Dis 2004 ; 190 (3) : 515-518. Epub 2004 Jul 07.

**Table 1.** Association between some Tropical Pulmonary Infectious Diseases and known Human Leukocyte Antigens

### **Author details**

**Disease Known HLA Influence Reference** *HLA-B\*49* Susceptible to

*HLA-B\*52* Susceptible to re-

*HLA-B\*45* Protecive against

*HLA-DQ\*6, HLA-DQB1\*0601* Protective in murine

*HLA-A\*33, HLA-HLA-Cw\*07* Susceptible to

*HLA-B\*18, HLA-Cw\*07* Susceptible to

**Table 1.** Association between some Tropical Pulmonary Infectious Diseases and known Human Leukocyte Antigens

Trypanosomiasis *HLA-B\*39, HLA-DR4, HLA-A\*30, HLA-DQB1\*0501, HLA-*

348 HLA and Associated Important Diseases

*DRB1\*01, HLA-DRB1\*08, HLA-DPB1\*0401, HLA— DPB1\*2301, HLA-DPB1\*3901, HLA-C\*03, HLA-A\*31, HLA-B\*39, HLA-DR8, HLA-DRB1\*0409, HLA-DRB1\*1503*

Toxoplasmosis *HLA-DQ\*3* Human

Dengue *HLA-A\*01, HLA-A\*0207, HLA-A\*24, HLA-B\*07, HLA-*

*DRB1\*07/\*15* genotype)

*HLA-A\*68, HLA-DR\*16, HLA-DQB1\*06, HLA-B\*40, HLA-DQB1\*0303, HLA-DRB1\*14, HLA-DRB1\*1501, HLA-DQ1, HLA-DQ3, HLA-DR4, HLA-DR5, HLA-DRB1\*0102, HLA-DRB\*1402, HLA-MICA\*011, HLA-DRB1\*1103*

*B\*46, HLA-B\*51, HLA-DQ\*1, HLA-DR\*1, HLA-DR\*4, HLA-A\*0211, HLA-Cw\*07* (in combination with *HLA-*

Leptospirosis *HLA-DQ\*6* Increased risk of

recurrent cutaneous leishmaniasis (American type)

infected cutaneous leishmaniasis American type)

cutaneous leishmaniasis (American type)

Susceptible to infection and development of Chagas' disease

Protective against development of chronic Chagas' cardiomyopathy and cardiac damage

hydrocephalus

Susceptible to development of dengue hemorrhagic

development of dengue fever

infection

laboratory confirmation

symptomatic dengue

model

fever

205

205

205

1, 216, 217, 222, 223, 224, 225, 227, 228

> 216, 217, 220, 225, 226, 227, 228

> > 249

249

263, 280, 281

281

281

296

Attapon Cheepsattayakorn1,2

Address all correspondence to: attaponche@yahoo.com

1 10th Zonal Tuberculosis and Chest Disease Centre, Chiang Mai, Thailand

2 10th Office of Disease Prevention and Control, Department of Disease Control, Ministry of Public Health, Thailand

### **References**


[9] Chiu RWK, Tang NL, Hui DS, Chung GT, Chim SSC, Chan KCA, *et al*. ACE2 gene polymorphisms do not affect outcome of severe acute respiratory syndrome. Clin Chem 2004 ; 50 (9) : 1683-1686.

[21] Tan EL, Ooi EE, Lin CY, Tan HC, Ling AE, Lim B, *et al*. Inhibition of SARS coronavi‐ rus infection *in vitro* with clinically approved antiviral drugs. Emerg Infect Dis 2004 ;

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

[22] Zheng B, He ML, Wong KL, Lum CT, Poon LL, Peng Y, *et al*. Potent inhibition of SARS-associated coronavirus (SCOV) infection and replication by type I interferons (IFN-alpha/beta) but not by type II interferon (IFN-gamma). J Interferon Cytokine

[23] Sainz JrB, Mossel EC, Peters CJ, Garry RF. Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associat‐

T-cell responses in recovered severe acute respiratory syndrome (SARS) pa‐

and

351

http://dx.doi.org/10.5772/58288

[24] Yang L, Peng H, Zhu Z, Gang L, Huang Z, Zhao Z, *et al*. Persistent memory CD4+

tients to SARS coronavirus M antigen. J Gen Virol 2007 ; 88 (Pt 10) : 2740-2748.

[25] Zhou M, Xu D, Li X, Li H, Shan M, Tang J, *et al*. Screening and identification of severe acute respiratory syndrome-associated coronavirus-specific CTL epitopes. J Immunol

[26] Selvaraj P. Host genetics and tuberculosis susceptibility. Curr Sci 2004 ; 86 (1) :

[27] Kim HS, Park MH, Song EY, Park H, Kwon SY, Han SK, et al. Association of HLA-DR and HLA-DQ genes with susceptibility to pulmonary tuberculosis in Koreans : preliminary evidence of association with drug resistance, disease severity, and dis‐

[28] Teran-Escandon D, Teran-Ortiz L, Camarena-Olvera A, Gonzalez-Avila G, Vaca-Marin MA, ranados J, et al. Human leukocyte antigen-associated susceptibility to pulmonary tuberculosis : molecular analysis of class II alleles by DNA amplification and oligonucleotide hybridization in Mexican patients. Chest 1999 ; 115 (2) : 428-433.

[29] Vejbaesya S, Chierakul N, Luangtrakool K, Srinak D, Stephens HA. Associations of HLA class II alleles with pulmonary tuberculosis in Thais. Eur J Immunol 2002 ; 29

[30] Selvaraj P, Sriram U, Mathan KS, Reetha AM, Narayanan PR. Tumor necrosis factor alpha (-238 and -308) and beta gene polymorphisms in pulmonary tuberculosis : hap‐ lotype analysis with HLA-A, B and DR genes. Tuberculosis (Edinb) 2001 ; 81 (5-6) :

[31] Li Y, Zhu Y, Zhou L, Fang Y, Huang L, Ren L, *et al*. Use of HLA-DR\*08032/E7 and HLA-DR\*0818/E7 tetramers in tracking of epitope-specific CD4+ T cells in active and convalescent tuberculosis patients compared with control donors. Immunobiology

ed coronavirus (SARS-Cov). Virology 2004 ; 329 (1) : 11-17.

ease recurrence. Hum Immunol 2005 ; 66 (10) : 1074-1081.

10 (4) : 581-586.

CD8+

115-121.

(5) : 431-434.

335-341.

2011 ; 216 (8) : 947-960.

Res 2004 ; 24 (7) : 388-390.

2006 ; 177 (4) : 2138-2145.


[21] Tan EL, Ooi EE, Lin CY, Tan HC, Ling AE, Lim B, *et al*. Inhibition of SARS coronavi‐ rus infection *in vitro* with clinically approved antiviral drugs. Emerg Infect Dis 2004 ; 10 (4) : 581-586.

[9] Chiu RWK, Tang NL, Hui DS, Chung GT, Chim SSC, Chan KCA, *et al*. ACE2 gene polymorphisms do not affect outcome of severe acute respiratory syndrome. Clin

[10] Hsieh Y-H, Chen CWS, Schmitz S-F H, King C-C, Chen W-J, Wu Y-C, *et al*. Candidate genes associated with susceptibility for SARS-coronavirus. Bull Math Biol 2009 ; 72

[11] Wang SF, Chen KH, Chen M, Li WY, Chen YJ, Tsao CH, *et al*. Human-leukocyte anti‐ gen class I Cw 1502 and class II DR 0301 genotypes are associated with resistance to severe acute respiratory syndrome (SARS) infection. Viral Immunol 2011 ; 24 (5) :

[12] Liu J, Wu P, Gao F, Qi J, Kawana-Tachikawa A, Xie J, *et al*. Novel immunodominant peptide presentation strategy : a featured HLA-A\*2402-restricted cytotoxic T-lym‐ phocyte epitope stabilized by intrachain hydrogen bonds from severe acute respira‐ tory syndrome coronavirus nucleocapsid protein. J Virol 2012 ; 84 (22) : 11849-11857.

[13] Chan VS, Chan KY, Chen Y, Poon LL, Cheung AN, Zheng B, *et al*. Homozygous LSIGN (CLEC4M) plays a protective role in SARS coronavirus infection. Nat Genet

[14] Ip WK, Chan KH, Law HK, Tso GH, Kong EK, Wong WH, *et al*. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis 2005 ;

[15] Hamano E, Hijikata M, Itoyama S, Quy T, Phi NC, Long HT, *et al*. Polymorphisms of interferon-inducible genes OAS-1 and MxA associated with SARS in the Vietnamese

[16] Haagmans BL, Kuiken T, Martina BE, Fouchier RA, Rimmelzwaan GF, Amerongen van, *et al*. Pegylated interferon-alpha protects type 1 pneumocytes against SARS co‐

[17] Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Treatment of

[18] Hensley LE, Frizt LE, Jahrling PB, Karp CL, Huggins JW, Geisbert TW. Interferon-be‐ ta 1a and SARS coronavirus replication. Emmerg Infect Dis 2004 ; 10 (2) : 317-319. [19] Spiegel M, Pichlmair A, Muhlberger E, Haller O, Weber F. The antiviral effect of in‐ terferon-beta against SARS-coronavirus is not mediated by MxA protein. J Clin Virol

[20] Stroher U, DiCaro A, Li Y, Strong JE, Aoki F, Plummer F, *et al*. Severe acute respoira‐ tory syndrome-related coronavirus is inherited by interferon-alpha. J Infect Dis 2004 ;

population. Biochem Biophys Res Commun 2005 ; 329 (4) : 1234-1239.

ronavirus infection in macaques. Nat Med 2004 ; 10 (3) : 290-293.

SARS with human interferons. Lancet 2003 ; 362 (9380) : 293-294.

Chem 2004 ; 50 (9) : 1683-1686.

421-426.

350 HLA and Associated Important Diseases

2006 ; 38 (1) : 38-46.

191 (10) : 1697-1704.

2004 ; 30 (3) : 211-213.

189 (7) : 1164-1167.

(1) : 122- 132. DOI : 10.1007/s11538-009-9440-8


[32] Daley CL. Pulmonary infections in the tropics : impact of HIV infection. Thorax 1994 ; 49 (4) : 370-378.

[46] Peeters P, Depre′ G, Rickaert F, Coremans-Pelseneer J, Serruys E. Disseminated Afri‐ can histolasmosis in a white heterosexual male patient with AIDS. Mykosen 1987 ; 30

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

353

[47] Depre′ G, Coremans-Pelseneer J, Peeters P, Rickaert F, Struelens M, Serruys E. Histo‐ plasmose africaine dissemenee associee a un syndrome d' immunodeficience ac‐

[48] Arendt V, Gerard M, Pelseneer J, Gottlob R, Clumeck N. African histoplasmosis in three HIV patients. In : VI International AIDS Conference. San Francisco : 1990, 396.

[49] Stansell J. Pulmonary fungal infections in HIV-infected persons. Sem Resp Infect dis

[50] Diamond R. The growing problem of mycoses in patients infected with the human

[51] Homberg K, Meyer R. Fungal infections in patients with AIDS and AIDS-related

[52] Kamanfu G, Mlika-Cabanne N, Girard P-M, Nimubona S, Mpfizi B, Cishako A, *et al*. Pulmonary complications of human immunodeficiency virus infection in Bujumbura,

[53] Serwadda D, Goodgame R, Lucas S, Kocjan G. Absence of pneumocystosis in Ugan‐

[54] Abouya YL, Beaumel A, Lucas S, Dago-Akribi A, Coulibaly G, N'Dhatz M, *et al*. Pneumocystis carinii pneumonia : an uncommon cause of death in African patients.

[55] Taelman H, Bogaerts J, Batungwanayo J, Van de Perre P, Lucas S, Allen S. Value of the cryptococcal serum antigen test in diagnosing pulmonary cryptococcosis in HIVinfected Rwandese patients. In : IX International Conference on AIDS. Berlin ; 1993,

[56] Taelman H, Batungwanayo J, Bogaerts J, Clerinx J, Kagame A, Van de Perre P. Main‐ tenance therapy with itraconazole prevents disseminated cryptococcal disease in HIV-infected patients with isolated pulmonary cryptococcosis. In : IX International

[57] Bogaerts J, Taelman H, Batungwanayo J, Van de Perre P, Swinne D. Two cases of HIV-associated crptococcosis due to the variety of gattii in Rwanda. Trans R Soc

[58] Goldani L, Coelho I, Machado A, Martinez R. Paracoccidioidomycosis and AIDS.

quise. Bull Soc Franc Mycol Med 1987 ; 16 (NA) : 75-80.

immunodeficiency virus. Rev Infect Dis 1991 ; 13 (3) : 480-486.

complex. Scand J Infect Dis 1986 ; 18 (NA) : 179-192.

Burundi. Am Rev Respir Dis 1993 ; 147 (3) : 658-663.

dan AIDS patients. AIDS 1989 ; 3 (1) : 47-48.

Am Rev Respir Dis 1992 ; 145 (3) : 617-620.

Conference on AIDS. Berlin ; 1993, 364.

Trop Med Hyg 1993 ; 87 (1) : 63-64.

Scand J Infect Dis 1991 ; 23 (3) : 393.

(10) : 449-453.

1993 ; 8 (2) : 116-123.

364.


[46] Peeters P, Depre′ G, Rickaert F, Coremans-Pelseneer J, Serruys E. Disseminated Afri‐ can histolasmosis in a white heterosexual male patient with AIDS. Mykosen 1987 ; 30 (10) : 449-453.

[32] Daley CL. Pulmonary infections in the tropics : impact of HIV infection. Thorax

[33] Singh KK, Spector SA. Host genetic determinants of human immunodeficiency virus infection and disease progression in children. Pediatr Res 2009 ; 65 (5 Pt 2) : 55R-63R.

[34] Mackelprang RD, John-Stewart G, Carrington M, Richardson B, Rowland-Jones S, Gao X, *et al.* Maternal HLA homozygosity and mother-child HLA concordance in‐ crease the risk of vertical transmission of HIV-1. J Infect Dis 2008 ; 197 (8) ; 1156-1161.

[35] Polycarpou A, Ntais C, Korber BT, Elrich HA, Winchester R, Krogstad P, *et al*. Asso‐ ciation between maternal and infant class I and II HLA alleles and of their concord‐ ance with the risk of perinatal HIV type 1 transmission. AIDS Res Hum Retroviruses

[36] O' Brien SJ, Gao X, Carrington M. HLA and AIDS : a cautionary tale. Trends Mol

[37] Carrington M, O' Brien SJ. The influence of HLA genotype on AIDS. Annu Rev Med

[38] Kuhn L, Abrams EJ, Palumbo P, Bulterys M, Aga R, Louie L, *et al*. Maternal versus paternal inheritance of HLA class I alleles among HIV-infected children : consequen‐

[39] Figueiredo JF, Rodrigues Mde L, Deghaide NH, Donadi EA. HLA profile in patients

[40] Gilks CF, Otieno LS, Brindle RJ, Newnham RS, Lule GN, Were JB, *et al*. The presenta‐ tion and outcome of HIV-related disease in Nairobi. Q J Med 1992 ; 82 (297) : 25-32.

[41] Javaly K, Horowitz HW, Wormser GP. Nocardiosis in patients with human immuno‐ deficiency virus infection ; report of 2 cases and review of the literature. Medicine

[42] Cheepsattayakorn A, Sutachai V. Identification of Burkholderia (Pseudomonas)

[43] Carme B, Itoua-Ngaporo A, Bourgarel J, Poste B. Histoplasma capsulatum histoplas‐ mosis. Apropos of a disseminated form with skin lesions in a woman from Zaire.

[44] Carme B, Ngolet A, Ebikili B, Itoua N. Is African histoplasmosis an opportunistic

[45] Carme B, Ngaporo A, Ngolet A, Ibara J, Ebikili B. Disseminated African histoplasmo‐ sis in a Congolese patient with AIDS. J Med Vet Myco 1992 ; 30 (3) : 245-248.

fungal infection in AIDS? Trans R Soc Trop Med Hyg 1990 ; 84 (2) : 293.

Zonal Tuberculosis and Chest Disease Center, Chiang Mai, Thai‐

ces for clinical disease progression. AIDS 2004 ; 18 (9) : 1281-1289.

with AIDS and tuberculosis. Bra J Infect Dis 2008 ; 12 (4) : 278-280.

1994 ; 49 (4) : 370-378.

352 HLA and Associated Important Diseases

2002 ; 18 (11) : 741-746.

Med 2001; 7 (9) : 379-381.

2003 ; 54 (NA) : 535-551.

(Bultimore) 1992 ; 71(3) : 128-138.

land. Thai J Tuberc Chest Dis 2001 ; 22 (2) : 105-111.

Bull Soc Pathol Exot Filiales 1984 ; 77 (5) : 653-657.

pseudomallei at 10th


[59] Bakos L, Kronfeld M, Hampe S, Castro I, Zampese M. Disseminated paracoccidioido‐ mycosis with skin lesions in a patient with acquired immunodeficiency syndrome. J Am Acad Dermatol 1989 ; 20 (5 Pt 1) : 854-855.

[71] Chequer P, Hearst N, Hudes E. Determinants of survival in adult Brazilian AIDS pa‐

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

355

[72] Kronfeld M, LeHugeur D, Rotbland A, de Quadros A, Dias D, dos Santos L, *et al*. Ac‐ quired immunodeficiency syndrome in the State of Rio Grand do Sul : a report of 40

[73] Elvin K, Lumbwe C, Luo N, Bjorkman A, Kallenius G, Linder E. Pneumocystis carinii is not a major cause of pneumonia in HIV-infected patients in Lusaka, Zambia. Trans

[74] Lucas S. Missing infections in AIDS. Trans R Soc Trop Med Hyg 1990 ; 84 (Suppl 1) :

[75] Genta R. Global prevalence of strongyloidiasis : critical review with epidemiologic insights into the prevention of disseminated disease. Rev Infect Dis 1989 ; 11(5) :

[76] Neto V, Pasternak J, Moreira A, Duarte M, Campos R, Braz L. Strongyloides stercora‐ lis hyperinfection in the acquired immunodeficiency syndrome. Am J Med 1989 ; 87

[77] Conlon C, Pinching A, Perera C, Moody A, Luo N, Lucas S. HIV-related enteropathy in Zambia : a clinical, microbiological, and histopathological study. Am Trop Med

[78] Vijayan VK. Tropical parasitic lung diseases. Indian J Chest Dis Allied Sci 2008 ; 50

[79] Scowden EB, Schaffner W, Stone WJ. Overwhelming strongyloidiasis : an unappreci‐

[80] Gompels MM, Todd J, Peters BS, Main J, Pinching AJ. Disseminated strongyloides in

[81] Armignacco O, Capecchi A, De Mori P. Strongyloides stercoralis hyperinfection and

[82] Maayan S, Wormser G, Widerhorn J, Sy E, Kim Y, Ernst J. Strongyloides stercoralis hyperinfection in a patient with the acquired immune deficiency syndrome. Am J

[83] Crompton DWT. How much human helminthiasis is there in the world ? J Parasitol

[84] Peng W, Zhou X, Gasser RB. Ascaris egg profile in human feces : biological and epi‐

demiological implications. Parasitology 2003 ; 127 (Pt 3) : 283-290.

ated opportunistic infection. Medicine (Baltimore) 1978 ; 57 (6) : 527-544.

the acquired immunodeficiency syndrome. Am J Med 1989 ; 86 (2) : 258.

AIDS : uncommon but important. AIDS 1991 ; 5 (3) : 329-332.

tients, 1982-1989. AIDS 1992 ; 6 (5) : 483-487.

R Soc Trop Med Hyg 1989 ; 83 (4) : 553-555.

34-38.

755-767.

(5) : 602-603.

(1) : 49-66.

Hyg 1990 ; 42 (1) : 83-88.

Med 1987 ; 83 (5) : 945-948.

1999 ; 85 (3) : 379-403.

cases. Rev Hosp Clin Porto Allegre 1988 ; 8 (NA) : 9-19.


[71] Chequer P, Hearst N, Hudes E. Determinants of survival in adult Brazilian AIDS pa‐ tients, 1982-1989. AIDS 1992 ; 6 (5) : 483-487.

[59] Bakos L, Kronfeld M, Hampe S, Castro I, Zampese M. Disseminated paracoccidioido‐ mycosis with skin lesions in a patient with acquired immunodeficiency syndrome. J

[60] Restrepo A. Paracoccidioides brasiliensis. In : Mandell G, Douglas R, Bennett J. (eds.) Principles and practice of infectious diseases. New York : Churchill Livingstone;

[61] Supparapinyo K, Chiewchanvit S, Hirunsri P. Uthammachai C, Nelson K, Sirisantha‐ na T. Penicillium marneffei infection in patients infected with human immunodefi‐

[62] Edman J, Kovacs J, Masur H, Santi D, Elwood H, Sogin M. Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi. Nature 1988 ; 334 (6182) :

[63] Smulian A, Sullivan D, Linke M, Halsey N, Quinn T, MacPhail A, *et al*. Geographic variation in the humoral response to Pneumocystis carinii. J Infect Dis 1993 ; 167 (5) :

[64] Meduri G, Stein D. Pulmonary manifestations of AIDS. Clin Infect Dis 1993 ; 14

[65] Cheepsattayakorn A, Punjaisri S, Chanwong S. Pneumocystis carinii pneumonia de‐ tection by sputum and blood polymerase chain reaction. Thai J Tuberc Chest Dis Crit

[66] Blaser M, Cohn D. Opportunistic infections in patients with AIDS : clues to the epi‐ demiology of AIDS and the relative virulence of pathogens. Rev Infect Dis 1986 ; 8

[67] Kreiss J, Castro K. Special consideration for managing suspected human immunode‐ ficiency virus infection and AIDS in patients from developing countries. J Infect Dis

[68] Malin A, Gwanzura L, Klein S, Musvaire P, Robertson V, Mason P. A bronchoscopic study of acute interstitial pneumonia in Zimbabwe ; difficulties in distinguishing Pneumocystis carinii pneumonia from disseminated pulmonary tuberculosis. In : IX

[69] Atzori C, Bruno A, Chichino G, Gatti S, Scaglia M. Pneumocystis carinii pneumonia and tuberculosis in Tanzanian patients infected with HIV. Trans R Soc Trop Med

[70] Pape JW, Liautaud B, Thomas F, Mathurin JR, St Amand MM, Boncy M, *et al*. The acquired immunodeficiency syndrome in Haiti. Ann Intern Med 1985 ; 103 (5) :

International Conference on AIDS. Berlin ; 1993, 431.

Am Acad Dermatol 1989 ; 20 (5 Pt 1) : 854-855.

ciency virus. Clin Infect Dis 1992 ; 14 (4) : 871-874.

1990 : p2018-2031.

354 HLA and Associated Important Diseases

519-522.

1243-1247.

(1) : 21-30.

(NA) : 98-113.

Care 2003 ; 24 (2) : 125-135.

1990 ; 162 (4) : 955-960.

Hyg 1993 ; 87(1) : 55-56.

674-678.


[85] Yazicioǧlu M, Ones U, Yalcin I. Peripheral and nasal eosinophilia and serum total immunoglobulin E levels in children with ascariasis. Turk J Pediatric 1996 ; 38 (4) : 477-484.

[100] Suwanik R, Harinasuta C. Pulmonary paragonimiasis : an evaluation of roentgen findings in 38 positive sputum patients in an endemic area in Thailand. Am J Roent‐

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

357

[101] Lee EG, Na BK, Bae YA, Kim SH, Je EY, Ju JW, *et al*. Identification of immunodomi‐ nant excretory-secretory cysteine proteases of adult Paragonimus westernmani by

[102] Na BK, Kim SH, Lee EG, Kim TS, Bae YA, Kang I, *et al*. Critical roles for excretorysecretory cysteine proteases during tissue invasion of Paragonimus westernmani

[103] Wongkham C, Intapan PM, Maleewong W, Miwa M. Evaluation of human IgG sub‐ class antibodies in the serodiagnosis of *Paragonimus heterotremus*. Asian Pac J Allergy

[104] Vele′z ID, Ortega JE, Vela′squez LE. Paragonimiasis : a review from Columbia. Clin

[105] Keiser J, Engels D, Buscher G, Utzinger J. Triclabendazole for treatment of fascioliasis and paragonimiasis. Expert Opin Investig Drugs 2005 ; 14 (12) : 1513-1526.

[107] Schwatz E, Rozenman J, Perelman N. Pulmonary manifestations of early Schistosoma

[109] Doherty JF, Moody AH, Wright SG. Katayama fever ; an acute manifestation of schis‐

[110] Nguyen LQ, Estrella J, Jett EA, Grunvald EL, Nocholson L, Levin DL. Acute schisto‐ somiasis in nonimmune travelers : chest CT findings in 10 patients. Am J Roentgenol

[111] Lapa MS, Ferreira EV, Jardim C, Martins BC, Arakaki JS, Souza R. Clinical character‐ istics of pulmonary hypertension patients in two reference centers in the city of Sao

[112] Morris W, Knauer M. Cardiopulmonary manifestations of schistosomiasis. Semin Re‐

[113] Sersar SI, Abulmaaty RA, Elnahas HA, Moussa SA, Shisa UA, Ghafar WA, *et al*. A diagnostic dilemma of right lower lobe collapse caused by pulmonary bilharsiasis.

[114] Gottstein B, Reichen J. Hydatid lung disease (echinococcosis/hydatidosis). Clin Chest

[106] Schwartz E. Pulmonary schistosomiasis. Clin Chest Med 2002 ; 23 (2) : 433-443.

infection in nonimmune travelers. Am J Med 2000 ; 109 (9) : 718-722.

[108] Walt F. The Katayama syndrome. A Afr Med J 1954 ; 28 (5) : 89-93.

tosomiasis. Br Med J 1996 ; 313 (7064) : 1071-1072.

Paulo. Rev Assoc Med Bras 2006 ; 52 (3) : 139-143.

newly excysted metacercariae. Cell Microbiol 2006 ; 8 (6) : 1034-1046.

proteome analysis. Proteomics 2006 ; 6 (4) : 1290-1300.

genol 1959 ; 81 (2) : 236-244.

Immunol 2005 ; 23 (4) : 205-211.

Chest Med 2002 ; 23 (2) : 421-431.

2006 ; 186 (5) : 1300-1303.

spir Infect 1997 ; 12 (2) : 159-170.

Heart Lung Circ 2006 ; 15 (1) : 50-52.

Med 2002 ; 23 (2) : 397-408.


[100] Suwanik R, Harinasuta C. Pulmonary paragonimiasis : an evaluation of roentgen findings in 38 positive sputum patients in an endemic area in Thailand. Am J Roent‐ genol 1959 ; 81 (2) : 236-244.

[85] Yazicioǧlu M, Ones U, Yalcin I. Peripheral and nasal eosinophilia and serum total immunoglobulin E levels in children with ascariasis. Turk J Pediatric 1996 ; 38 (4) :

[86] Santra A, Bhattacharya T, Chowdhury A, Ghosh A, Ghosh N, Chatterjee BP, et al. Se‐ rodiagnosis of ascariasis with specific IgG4 antibody and its use in epidemiological

[87] Loffler W. Zur differential-diagnose der lungeninfiltrieurgen : 11 Uber fluchtige suc‐ cedan-infiltrate (mit eosinophile). Bietr Klin Tuberk 1932 ; 19 (NA) : 368-392.

[88] Ford RM. Transient pulmonary eosinophilia and asthma : a review of 20 cases occur‐

[89] Liu LX, Weller PF. Strongyloidiasis and other intestinal nematode infections. Infect

[90] Citro LA, Gordon ME, Miller WT. Eosinophilic lung disease (or how to slice PIE).

[91] Hoagland KE, Schad GA. Necator americanus and Ancylostoma duodenale : life his‐ tory parameters and epidemiological implications of two sympatric hookworms on

[92] Hotez P. Human hookworm infection. In : Farthing MJG, Keusch GT, Wakelin D. (eds.) Intestinal Helminths. London : Chapman and Hall ; 1995. p129-150.

[93] Nawalinski TA, Schad GA. Arrested development in Ancylostoma duodenale : cause of self-induced infections in man. Am J Trop Med Hyg 1974 ; 23 (5) : 895-898.

[94] Cappello M, Clyne LP, MacPhedram P, Hotez PJ. Ancylostoma factor Xa inhibitor : partial purification and its identification as a major hookworm-derived anticoagulant

[95] Nakamura-Uchiyama F, Mukae H, Nawa Y. Paragonimiasis : a Japanese perspective.

[96] Blair D, Xu ZB, Agatsuma T. Paragonimiasis and the genus paragonimus. Adv Para‐

[97] King CH. Pulmonary flukes. In : Mahamoud AAF. (ed.) Lung Biology in Health and Disease : Parasitic Lung Disease. New York : Marcel Dekker ; 1997. p157-169.

[98] Xu ZB. Studies on clinical manifestations, diagnosis and control of paragonimiasis in China. Southeast Asian J Trop Med Pub Health 1991 ; 22 (Suppl. 1) : 345-348.

[99] Mukae H, Taniguchi H, Matsumoto N, Liboshi H, Ashitani J, Matsukura S, *et al*. Clin‐ icoradiological features of pleuropulmonary Paragonimiasis (westernmani) on

ring in 5,702 asthma sufferers. Am Rev Respir Dis 1996 ; 93 (5) : 797-803.

Am J Roentgenol Rad Ther Nuc Med 1973 ; 117 (NA) : 787-797.

study. Trans R Soc Trop Med Hyg 2001 ; 95 (3) : 289-292.

Dis Clin North Am 1993 ; 7 (3) : 655-682.

humans. Exp Parasitol 1978 ; 44 (1) : 36-49.

in vitro. J Infect Dis 1993 ; 167 (6) : 1474-1477.

Kyushu Island, Japan. Chest 2001 ; 120 (NA) : 514-520.

Clin Chest Med 2002 ; 23 (2) : 409-420.

sitol 1999 ; 42 (NA) : 113-222.

477-484.

356 HLA and Associated Important Diseases


[115] Kuzucu A. Parasitic diseases of the respiratory tract. Curr Opin Pulm Med 2006 ; 12 (3) : 212-221.

[128] Engvall E, Ljungstrom I. Detection of human antibodies to Trichinella spiralis by en‐ zyme- linked immunosorbent assay (ELISA). Acta Pathol Microbiol Scand 1975 ; 83

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

359

[129] Vijayan VK. Tropical pulmonary eosinophilia : pathogenesis, diagnosis and manage‐

[130] Ottesen EA. Immunological aspects of lymphatic filariasis and onchocerciasis. Trans

[131] Frimodt-Mǒller C, Barton RM. A pseudo-tuberculosis condition associated with eo‐

[133] Kamat SR, Pimparkar SD, Store SD, Warrier NVU, Fakey YC. Study of clinical, radio‐ logical and pulmonary function patterns and response to treatment in pulmonary eo‐

[134] Basu SP. X-ray appearance in lung fields in tropical eosinophilia. Indian Med Gaz

[135] Islam N, Huque KS. Radiological features of tropical eosinophilia. J Trop Med Hyg

[136] Khoo FY, Danaraj TJ. The roentgenographic appearance of eosinophilic lung (tropical eosinophilia). Am J Roentgenol Radium Ther Nucl Med 1960 ; 86 (NA) : 251-259.

[137] World Health Organization, Division of Control of Tropical Diseases. Lymphatic fi‐ lariasis infection and disease : control strategies, 1994 (TDR/CTD/FIL/Penang) ; p1-30.

[138] Sandhu M, Mukhopadhyay S, Sharma SK. Tropical pulmonary eosinophilia : a com‐ parative evaluation of plain chest radiography and computed tomography. Australas

[139] Johnson S, Wilkinson R, Davidson RN. Tropical respiratory medicine. IV : Acute

[140] Ottensen EA, Nutman TB. Tropical pulmonary eosinophilia. Ann Rev Med 1992 ; 43

[141] Danaraj TJ, Schacher JF. I/D test with Dirofilaria immitis extract in eosinophilic lung

[142] Webb JKB, Job OK, Gault EW. Tropical eosinophilia : demonstration of microfilariae

[143] Joshi VV, Udwadia FE, Gadgil RK. Etiology of tropical eosinophilia : a study of lung biopsies and review of published reports. Am J Trop Med Hyg 1969 ; 18 (2) : 231-240.

tropical infection and the lung. Thorax 1994 ; 49 (NA) : 714-718.

(tropical eosinophilia). Am J Trop Med Hyg 1959 ; 8 (6) : 640-643.

in lung, liver and lymph nodes. Lancet 1960 ; 275 (7129) : 835-842.

ment. Curr Opin Pulm Med 2007 ; 13 (5) : 428-433.

sinophilia. Indian Med Gaz 1940 ; 75 (10) : 607-613.

sinophilia. Indian J Chest Dis 1970 ; 12 (3) : 91-100.

[132] Weingarten RJ. Tropical eosinophilia. Lancet 1943 ; 1 (NA) : 103-105.

R Soc Trop Med Hyg 1984 ; 73 (suppl) : 9-18.

(NA) : 231-237.

1954 ; 89 (NA) : 212-217.

1965 ; 68 (NA) : 117-180.

Radiol 1996 ; 40 (1) : 32-37.

(NA) : 417-424.


[115] Kuzucu A. Parasitic diseases of the respiratory tract. Curr Opin Pulm Med 2006 ; 12

[116] Fanne RA, Khamaisi M, Mevorach D, Leitersdorf E, Berkman N, Laxer U, *et al*. Spon‐ taneous rupture of lung echinococcal cyst causing anaphylactic shock and respirato‐

[117] Savani DM, Sharma OP. Eosinophilic lung disease in the tropics. Clin Chest Med

[118] Ito A, Sako Y, Yamasaki H, Mamuti W, Nakaya K, Nakao M, *et al*. Development of Em 18- immunoblot and Em 18-ELISA for specific diagnosis of alveolar echinococco‐

[119] Gencer M, Ceylan E. Pulmonary echinococcosis with multiple nodules mimicking metastatic lung tumor in chest radiography. Respiration. http:// www.ncbi.nlm.nih.gov/sites/entrez/ (accessed 30 August 2013). DOI :

[120] Asanuma T, Kawahara T, Inanami O, Nakao M, Nakaya K, Ito A, *et al*. Magnetic res‐ onance imaging of alveolar echinococcosis experimentally induced in the rat lung. J

[121] Gottstein B, Reichen J. Hydatid lung disease. In : Sharma OP (ed.) Lung Biology in Health and Disease : Tropical Lung Disease ; 2nd ed. New York : Taylor and Francis

[122] Kavukcu S, Kilic D, Tokat AO, Kutlay H, Cangir AK, Enon S, *et al*. Parenchyma-pre‐ serving surgery in the management of pulmonary hydatid cysts. J Invest Surg 2006 ;

[123] Hasdiraz L, Oǧuzkaya F, Bilgin M. Is lobectomy necessary in the treatment of pul‐

[124] Dincer SI, Demir A, Sayar A, Gunluoglu MZ, Kara HV, Gurses A. Surgical treatment of pulmonary hydatid disease : a comparison of children and adults. J Pediatr Surg

[125] Pozio E, La Rosa G, Murrell KD, Lichtenfels JR. Taxonomic revision of genus Trichi‐

[126] Despommier DD. How does Trichinella spiralis make itself at home? Parasitol Today

[127] Bruschi F, Murrell K. Trichinellosis. In : Guerrant RL, Walker DH, Weller PF. (eds.) Tropical Infectious Diseases : Principles, Pathogens and Practice ; Vol. II. Philadel‐ phia : Churchill Livingstone (Elsevier Science Health Science Divn) ; 1999. p917-925.

monary hydatid cysts? ANZ J Surg 2006 ; 76 (6) : 488-490.

ry distress syndrome. Thorax 2006 ; 61 (6) : 550.

(3) : 212-221.

358 HLA and Associated Important Diseases

2002 ; 23 (2) : 377-396.

10.1159/000091141.

sis. Acta Trop 2003 ; 85 (2) : 173-182.

Vet Med Sci 2006 ; 68 (1) : 15-20.

Group ; 2006. p327-350.

2006 ; 41 (7) : 1230-1236.

1998 ; 14 (8) : 318-323.

nella. J Parasitol 1992 ; 78 (4) : 654-659.

19 (1) : 61-68.


[144] Danaraj TJ, Pachecco G, Shanmugaratnam K, Beaver PC. The etiology and pathology of eosinophilic lung (tropical eosinophilia). Am J Trop Med Hyg 1966 ; 15 (2) : 183-189.

[157] Ganatra RD, Sheth UK, Lewis RA. Diethylcarbamazine (Hetrazan) in tropical eosino‐

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

361

[158] Baker SJ, Rajan KT, Davadutta S. Treatment of tropical eosinophilia : a controlled tri‐

[159] Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut K, Choti‐ vanich K, Newton PN, *et al*. Estimation of the total parasite biomass in acute falcipa‐ rum malaria from plasma PfHRP2. PLoS Med 2005 ; 2 (8) : e204. DOI : 10.1371/

[160] Hananantachai H, Patarapotikul J, Ohashi J, Naka I, Looareesuwan S, Tokunaga K. Polymorphisms of the HLA-B and HLA-DRB1 genes in Thai malaria patients. Jpn J

[161] Hirayasu K, Ohashi J, Kashiwase K, Hananantachai H, Naka I, Okawa A, *et al*. Signif‐ icant association of KIR2DL3-HLA-C1 combination with cerebral malaria and impli‐ cations for co-evolution of KIR and HLA. PLoS Pathog 2012 ; 8(3) : e1002565. DOI :

[162] Young K, Frodsham A, Doumbo OK, Gupta S, Dolo A, Hu JT, *et al*. Inverse associa‐ tions of human leukocyte antigen and malaria parasite types in two West African

[163] Hill AVS, Allsopp CEM, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, *et al*. Common West African HLA antigens are associated with protection from severe ma‐

[164] May J, Meyer CG, Kun JFJ, Lell B, Luckner D, Dippmann AK, *et al*. HLA class II fac‐ tors associated with Plasmodium falciparum merozoite surface antigen allele fami‐

[165] Maquire GP, Handojo T, Pain MC, Kenangalem E, Price RN, Tjitra E, *et al*. Lung in‐ jury in uncomplicated and severe falciparum malaria : a longitudinal study in Papua,

[166] Mharakurwa S, Simoloka C, Thuma PE, Shiff CJ, Sullivan DJ. PCR detection of Plas‐ modium falciparum in human urine and saliva samples. Malar J 2006 Nov 8 ; 5

[167] Djimde′ A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, Diourte Y, *et al*. A mo‐ lecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 2001 ; 344

[168] Laufer MK, Thesing PC, Eddington ND, Masonga R, Dzinjalamala FK, Takala SL, *et al*. Return of chloroqiune antimalarial efficacy in Malawi. N Engl J Med 2006 ; 355

philia. India J Med Resi 1958 ; 46 (2) : 205-222.

al. Lancet 1959 ; 274 (7095) : 144-147.

journal.pmed.0020204

Infect Dis 2005 ; 58 (1) : 25-28.

10.1371/journal.ppat.1002565

populations. Infect. Immun. 2005 ; 73 (2) : 953-955.

laria. Nature 1991 ; 352 (6336) : 595-600.

lies. J Infect Dis 1999 ; 179 (4) : 1042-1045.

(NA) : 103. DOI :10.1186/1475-2875-5-103

(4) : 257-263.

(19) : 1959-1966.

Indonesia. J Infect Dis 2005 ; 192 (11) : 1966-1974.


[157] Ganatra RD, Sheth UK, Lewis RA. Diethylcarbamazine (Hetrazan) in tropical eosino‐ philia. India J Med Resi 1958 ; 46 (2) : 205-222.

[144] Danaraj TJ, Pachecco G, Shanmugaratnam K, Beaver PC. The etiology and pathology of eosinophilic lung (tropical eosinophilia). Am J Trop Med Hyg 1966 ; 15 (2) :

[145] Steel C, Nutman TB. Altered T-cell Memory and effector cell development in chronic lymphatic filarial infection that is independent of persistent parasite antigen. PLoS

[146] Lal RB, Kumaraswami V, Krishnan N, Nutman TB, Ottesen EA. Lymphocyte subpo‐

[147] Sasisekhar B, Aparna M, Augustin DJ, Kaliraj P, Kar SK, Nutman TB, *et al*. Diminish‐ ed momnocyte function in microfilaremic patients with lymphatic filariasis and its relationship to altered lymphoproliferative responses. Imfect Immun 2005 ; 73 (6) :

[148] Chan SH, Dissanayake S, Mak JW, Ismail MM, Wee GB, Srinivasan N, *et al*. HLA and filariasis in Sri Lankans and Indians. The Southeast Asian J Trop Med Public Health

[149] Ottesen EA, Neva FA, Paranjape RS, Tripathy SP, Thiruvengadam KV, Beaver MA. Specific allergic sensitization to filarial antigens in tropical pulmonary eosinophilia.

[150] Viswanathan R, Bagai RC, Raran R. Leukocyte adhesion phenomenon in pulmonary eosinophilia (tropical eosinophilia). Am Rev Respir Dis 1973 ; 107 (NA) : 298-300.

[151] Dreyer G, Noroes J, Rocha A, Addiss D. Detection of living adult *Wuchereria bancrofti* in a patient with tropical eosinophilia. Braz J Med Biol Res 1996 ; 29 (NA) : 1005-1008.

[152] Perera CS, Perera LM, de Silva C, Abeywickreme W, Dissanaike AS, Ismail MM. An eosinophilic granuloma containing an adult female *Wuchereria bancrofti* in a patient

[153] Nutman TB, Vijayan VK, Pinkston P, Steel R, Crystal RG, Ottesen EA. Tropical pul‐ monary eosinophilia : analysis of antifilarial antibody localized to the lung. J Infect

[154] Vijayan VK. Tropical eosinophilia : bronchoalveolar lavage and pulmonary patho‐ physiology in relation to treatment. PhD thesis. University of Madras, Madras, India;

[155] Vijayan VK, Kuppurao KV, Sankaran K, Venkatesan P, Prabhakar R. Tropical eosino‐ philia : clinical and physiological response to diethylcarbamazine. Respir Med 1991 ;

[156] World Health Organization. Final report : Joint WPRO/SEARO Working Group on

with tropical eosinophilia. Trans R Soc Trop Med Hyg 1992 ; 86 (5) : 542.

chronic lymphatic obstruction. Clin Exp Immunol 1989 ; 77 (1) : 77-82.

) CD8+


ONE 2011 ; 6 (4) : e19197. DOI : 10.1371/journal.pone.0019197

pulations in Bancroftian filariasis : activated (DR+

183-189.

360 HLA and Associated Important Diseases

3385-3393.

1984 ; 15 (3) : 281-286.

Lancet 1979 ; 314 (8153) : 1158-1161.

Dis 1989 ; 160 (6) : 1042-1050.

Brugian Filariasis. Manila : WHO ; 1979. p1-47.

1988.

85 (1) : 17-20.


[169] Mutabingwa TK. Artemisinin-based combination therapies (ACTs) : best hope for malaria treatment but inaccessible to the needy! Acta Trop 2005; 95 (3) : 305-315.

[183] Garcia-Rubio I, Martinez-Cocera C, Santos Magadan S, Rodriguez-Jimenez B, Vas‐ quez-cortes S. Hypersentivity reactions to metronidazole. Allergol Immunopathol

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

363

[184] Leo′n-Sicairos N, Reyes-Lo′pez M, Ordaz-Pichardo C, de la Garza M. Microbicidal action of lactoferrin and lactoferricin and their synergic effect with metronidazole in

[185] Lotter H, Tannich E. The current status of an amoebiasis vaccine. Arch Med Res

[186] Basu R, Roy S, Walden P. HLA class I-restricted T-cell epitopes of the kinetoplastid membrane protein-11 presented by Leishmania donovani-infected human macro‐

[188] Russo R, Laguna F, Lopez-Velez R, Medrano FJ, Roenthal E, Cacopardo B, *et al*. Vis‐ ceral leishmaniasis in those infected with HIV : clinical aspects and other opportunis‐

[189] Benzie AA, Goldin RD, Walsh J. A case report of seronegative pulmonary leishma‐ niasis in an HIV-hepatitis C co-infected patient. HIV Med 2006 ; 7 (Suppl. 1) : 36 (ab‐

[190] Alvar J, Aparicio P, Aseffa A, Boer MD, Cañavate C, Dedet JP, et al. The relationship between leishmaniasis and AIDS : the second 10 years. Clin Microbiol Rev 2008 ; 21

[191] Barreto-de-Souza V, Pacheo GJ, Silva AR, Castro-Faria-Neto HC, Bozza PT, Saraiva EM, *et al*. Increased leishmania replication in HIV-1-infected macrophages is mediat‐ ed by tat protein through cyclooxygenase-2 expression and prostaglandin E 2 synthe‐

[192] Cota GF, de Sousa MR, Rabello A. Predictors of visceral leishmaniasis relapse in HIV-infected patients : a systematic review. PLoS Negl Trop Dis 2011 ; 5 (6) : Article

[193] Santos-Oliveira JR, Giacoia-Gripp CBW, de Oliveira PA, Amato VS, Lindoso JA, Goto H, *etal*. High levels of T-lymphocyte activation in Leishmania-HIV-1 co-infected indi‐

[194] Alexandro-de-Oliveira P, Santos-Oliveira JR, Dorval MEC, Da-Costa Fd, Pereira GR, da Cunha RV, *et al*. HIV/AIDS-associated visceral leishmaniasis in patients from an endemic area in Central-west Brazil. Mem Inst Oswaldo Cruz 2010 ; 105 (5) : 692-697.

[195] Morales P, Torres JJ, Salavert M, Pema′n J, Lacruz J, Sole′ A, *et al*. Visceral leishma‐ niasis in lung transplantation. Transplantation Proc 2003 ; 35 (5) : 2001-2003. [196] LeishGEN Consortium ; Wellcome Trust Case Control Consortium, Fakiola M, Strange A, Cordell HJ, Miller EN, Pirinen M, Su Z, *et al*. Common variants in the

viduals despite low HIV viral load. BMC Infect Dis 2010 ; 10 (NA) : 358-363.

[187] Piscopo TV, Mallia AC. Leishmaniasis. Postgrad Med J 2006 ; 82 (972) : 649-657.

tic infections. Ann Trop Med Parasitol 2003 ; 97 (Suppl.1) : S99-S105.

Entamoeba histolytica. Biochem Cell Biol 2006 ; 84 (3) : 327-336.

phages. J Infect Dis 2007 ; 195 (9) : 1378-1380.

sis. J Infect Dis 2006 ; 194 (6) : 846-854.

(Madr) 2006 ; 34 (2) : 70-72.

2006 ; 37 (2) : 292-296.

stract no. P100).

(2) : 334-359.

ID e1153.


[183] Garcia-Rubio I, Martinez-Cocera C, Santos Magadan S, Rodriguez-Jimenez B, Vas‐ quez-cortes S. Hypersentivity reactions to metronidazole. Allergol Immunopathol (Madr) 2006 ; 34 (2) : 70-72.

[169] Mutabingwa TK. Artemisinin-based combination therapies (ACTs) : best hope for malaria treatment but inaccessible to the needy! Acta Trop 2005; 95 (3) : 305-315. [170] World Health Organization. Guidelines for the treatment of malaria. Geneva : World

[171] World Health Organization. Management of severe malaria : a practical handbook, 3rd ed. WHO ; 2012. http://www.who.int/malaria (accessed 16 December 2013). [172] Kiang KM, Bryant PA, Shingadia D, Ladhani S, Steer AC, Burgner D. The treatment of imported malaria in children : an update. Arch Dis Child Educ Prac Ed 2013 ; 98

[173] Greenwood BM, Bojang K, Whitty CJ, Targett GA. Malaria. Lancet 2005 ; 365 (9469) :

[174] Ackers JP, Mirelman D. Progress in research on Entamoeba histolytica pathogenesis.

[175] Shamsuzzaman SM, Hashiguchi Y. Thoracic amoebiasis. Clin Chest Med 2002 ; 23

[176] Duggal P, Guo X, Haque R, Peterson KM, Rickklefs S, Mondal D, et al. A mutation in the Leptin receptor is associated with Entamoeba histolytica infection in children. J

[177] Marie CS, Verkerke HP, Paul SN, Mackey AJ, Petri WA Jr. Leptin protects host cells from Entamoeba histolytica cytotoxicity by a STAT3-dependent mechanism. Infect

[178] Duggal P, Haque R, Roy S, Mondal D, Sack RB, Farr BM, et al. Influence of human leukocyte antigen class II alleles on susceptibility to Entamoeba histolytica infection in Bangladeshi children. J Infect Dis 2004; 189 (3) : 520-526. DOI : 10.1128/IAI.

[179] Moonah SN, Jiang NM, Petri WA Jr. Host immune response to intestinal amoebiasis.

[180] Hamzah Z, Petmitr S, Mungthin M, Leelayoova S, Chavalitshewinkoon-Petmitr P. Differential detection of Entamoeba histolytica, Entamoeba dispar and Entamoeba moshkovskii by a single-round PCR assay. J Clin Microbiol 2006 ; 44 (9) : 3196-3200.

[181] Haque R, Petri WA Jr. Diagnosis of amoebiasis in Bangladesh. Arch Med Res 2006 ;

[182] Tanyuksel M, Petri WA Jr. Laboratory diagnosis of amoebiasis. Clin Microbiol Rev

PLoS Pathog 2013 ; 9 (8) : e1003489. DOI : 10.1371/journal.ppat.1003489

Clin Invest 2011 ; 121 (3) : 1191-1198. DOI : 10.1172/JC145294

Health Organization ; 2006. p1-266.

Curr Opin Microbiol 2006 ; 9 (4) : 367-373.

Immun 2012 ; 80 (5) : 1934-1943.

(1) : 7-15.

362 HLA and Associated Important Diseases

1487-1498.

(2) : 479-492.

06140-11

37 (2) : 273-276.

2003 ; 16 (4) : 713-729.


HLADRB1-HLA-DQA1 HLA class II region are associated with susceptibility to vis‐ ceral leishmaniasis. Nat Genet 2013 ; 45 (2) : 208-213.

[209] Bouteille B, Buguet A. The detection and treatment of human African trypanosomia‐

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

365

[210] Ayub M, Shah SA, Irfan M, Khan JA, Hashmi SN. A case of human African trypano‐ somiasis during United Nation Mission in Liberia. Pak. Armed. Forces. Med. J. 2011 ; 8 (1) : NA. http://www.pafmj.org/showdetails.php?id=187&t=c (accessed 26 Decem‐

[211] Melnikov VG, Velasco FF, Go′mez FE, Rodriguez FG, Dobrovinskaya OR. Pathologic changes in lungs caused by Mexican isolates of Trypanosoma cruzi in the acute

[212] Ši′ma M, Havelkova′ H, Quan L, Svobodova′ M, Jaroši′kova′ T, Vojti′škova′ J, *et al*. Genetic control of resistance to Trypanosoma brucei infection in mice. PLoS Negl

[213] Biswas D, Choudhury A, Misra KK. Histopathology of Trypanosoma (Trypanosoon) evani infection in bandicoot rat I visceral organs. Exp Parasitol 2001 ; 99 (3) : 148-159.

[214] Nuñes Mdo C, Barbosa Mde M, Brum VA, Rocha MO. Morphofunctional characteris‐ tics of the right ventricle in Chagas' dilated cardiomyopathy. Int J Cardiol 2004 ; 94

[215] Ayo CM, Dalalio MMdeO, Visentainer JEL, Reis PG, Sippert EA, Jarduli LR, *et al*. Ge‐ netic susceptibility to Chagas' disease : an overview about the infection and about the association between disease and the immune response genes. Biomed Res Int

[216] Cruz-Robles D, Reyes PA, Monteo′n-Padilla VM, Ortiz-Muñiz AR, Vargas-Alarco′n G. MHC class I and class II genes in Mexican patients with Chagas' disease. Hum Im‐

[217] Deghaide NH, Dantas RO, Donadi EA. HLA class I and II profiles of patients pre‐

[218] de Oliveira Dala′lio MM, Vissentainer JEL, Moliterno RA, Sell AM, Petzel-Erler ML. Association of HLA-DR2 with chronic chagasic cardiopathy in a population at Para‐

[219] Fae′ KC, Drigo SA, Cunha-Neto E, Ianni B, Mady C, Kalil J, *et al*. HLA and β-myosin heavy chain do not influence susceptibility to Chagas' disease cardiomyopathy. Mi‐

[220] Llop E, Rothhammer F, Acuña M, Apt W. HLA antigens in cardiomyopathic Chilean

[221] Llop E, Rothhammer F, Acuña M, Apt W, Arribada A. HLA antigens in Chagas car‐ diomyopathy : new evidence-based on a case-control study. Rev Med Chil 1991 ; 119

2013 ; Article ID 284729, 13 pages. http://dx.doi.org/10.1155/2013/284729

senting with Chagas' disease. Dig Dis Sci 1998 ; 43 (2) : 246-252.

na′ Northeast region, Brazil. Acta Scientiarum 2002 ; 24 (3) : 727-730.

phase of infection in mice. Am J Trop Med Hyg 2005 ; 73 (2) : 301-306.

sis. Res. Rep. Trop. Med. 2012 ; 3 (NA) : 35-45.

ber 2013).

(1) : 79-85.

Trop Dis 2011 ; 5 (6) : e1173.

munol 2004 ; 65(1) : 60-65.

crobes Infect 2000 ; 2 (7) : 745-751.

(6) :633-636.

chagasics. Am J Hum Genet 1988 ; 43 (5) : 770-773.


[209] Bouteille B, Buguet A. The detection and treatment of human African trypanosomia‐ sis. Res. Rep. Trop. Med. 2012 ; 3 (NA) : 35-45.

HLADRB1-HLA-DQA1 HLA class II region are associated with susceptibility to vis‐

[197] Blackwel JM, Freeman J, Bradley D. Influence of H-2 complex on acquired resistance to Leishmania donovani infection in mice. Nature 1980 ; 283 (5742) : 72-74.

[198] Blackwel JM. Leishmania donovani infection in heterozygous and recombinant H-2

[199] Blackwel JM, Roberts MB. Immunomodulation of murine visceral leishmaniasis by administration of monoclonal anti-Ia antibodies : differential effects of anti-I-A vs an‐

[200] Polley R, Stager S, Prickett S, Maroof A, Zubairi S, Smith DF, *et al*. Adoptive immu‐ notherapy against experimental visceral leishmaniasis with CD8+ T-cells requires the

[201] Stern JJ, Oca MJ, Rubin BY, Anderson SL, Murray HW. Role of L3T4+ and LyT-2+ cells in experimental visceral leishmaniasis. J Immunol 1988 ; 140 (11) : 3971-3977.

[202] Medddeb-Garnaoui A, Gritli S, Garbouj S, Ben Fadhel M, El kares R, Mansour L, *et al*. Association analysis of HLA class II and class III gene polymorphisms in the suscept‐ ibility to Mediterranean visceral leishmaniasis. Hum Immunol 2001 ; 62 (5) : 509-517.

[203] Karplus TM, Jeronimo SM, Chang H, Helms BK, Burns TL, Murray C, *et al*. Associa‐ tion between the tumor necrosis factor locus and the clinical outcome of Leishmania/

[204] Blackwell JM, Jamieson SE, Burgner D. HLA and infectious diseases. Clin Microbiol

[205] Ribas-Silva RC, Ribas AD, dos Santos MCG, da Silva Jr WV, Lonardoni MVC, Borelli SD, *et al.* Association between HLA genes and American cutaneous leishmaniasis in endemic regions of southern Brazil. BMC Infect Dis 2013 ; 13 (NA) : 198. DOI :

[206] Santos-Oliveira JR, Da-Cruz AM. Lipopolysaccharide-induced cellular activation may participate in the immunopathogenesis of visceral leishmaniasis alone or in HIV co-infection. Int J Microbiol 2012, Article ID 364534, 4 pages. DOI :

[207] Croft SL, Engel J. Miltefosine : discovery of the antileishmanial activity of phospholi‐

[208] Sachdeva R, Banerjea AC, Malla N, Dubey ML. Immunogenicity and efficacy of sin‐ gle antigen Gp63, polytope and polytopeHSP70 DNA vaccines against visceral leish‐ maniasis in experimental mouse model. PLoS ONE 2009 ; 4 (12) : e7880. DOI :

pid derivatives. Trans R Soc Trop Med Hyg 2006 ; 100 (Suppl. 1) : 54-58.

ceral leishmaniasis. Nat Genet 2013 ; 45 (2) : 208-213.

364 HLA and Associated Important Diseases

haplotype mice. Immunogenetics 1983 ; 18 (2) : 101-109.

ti-I-E antibodies. Eur J Immonol 1987 ; 17 (11) : 1669-1672.

chagasi infection. Infect Immun 2002 ; 70 (12) : 6919-6925.

Rev 2009 ; 22 (2) : 370-385.

10.1186/1471-2334-13-198

10.1155/2012/364534

10.1371/journal.pone.0007880

presence of cognate antigen. Infect Immun 2006 ; 74 (1) : 773-776.


[222] Fernandez-Mestre MT, Layrisse Z, Montagnani S, Acquatella H, Catalioti F, Mastos M, *et al*. Influence of HLA class II polymorphism in chronic Chagas' disease. Parasite Immunol 1998 ; 20 (4) : 197-203.

[234] Feldman GJ, Parker HW. Visceral larval migrans associated with the hypereosino‐ philic syndrome and the onset of severe asthma. Ann Intern Med 1992 ; 116 (10) :

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

367

[235] Roig J, Romeu J, Riera C, Texido A, Domingo C, Morera J. Acute eosinophilic pneu‐ monia due to toxocariasis with bronchoalveolar lavage findings. Chest 1992 ; 102 (1) :

[236] Bartelink AK, Kortbeek LM, Huidekoper HJ, Meulenubelt J, van Knapen F. Acute respiratory failure due to toxocara infections. Lancet 1993 ; 342 (8881) : 1234.

[237] Magnaval JF, Glickman LT, Dorchies P, Morassin B. Highlights of human toxocaria‐

[238] Glickman LT, Magnaval JF, Domanski LM, Shofer FS, Lauria SS, Gottstein B, *et al*. Visceral larval migrans in French adults : a new disease syndrome ? Am J Epidemiol

[239] Nathwani D, Laing RB, Currie PF. Covert toxocariasis-a cause of recurrent abdomi‐

[240] Magnaval JF, Fabre R, Maurieres P, Charlet JP, de Larrard B. Evaluation of an immu‐ nenzymatic assay detecting specific anti-Toxocara immunoglobulin E for diagnosis and post-treatment follow-up of human toxocariasis. J Clin Microbiol 1992 ; 30 (9) :

[241] Magnaval JF, Fabre R, Maurieres P, Charlet JP, de Larrard B. Application of the West‐ ern-blotting procedure for the immunodiagnosis of human toxocariasis. Parasitol Res

[242] Rasmussen LN, Dirdal M, Birkeback NH. Covert toxocariasis in a child treated with

[243] Magnaval JF. Comparative efficacy of diethylcarbamazine and mebendazole for the treatment of human toxocariasis. Parasitology 1995 ; 110 (Pt 5) : 529-533.

[244] Sturchler D, Schubarth P, Gualzata M, Gottstein B, Orettli A. Thiabendazole vs alben‐ dazole in treatment of toxocariasis : a clinical trial. Ann Trop Med Parasitol 1989 ; 83

[246] Monso′ E, Vidal R, de Gracia X, Moragas A. Pulmonary toxoplasmoma presenting as

[247] Nash G, Kerschmann RL, Herndier B, Dubey JP. The pathological manifestations of pulmonary toxoplasmosis in the acquired immunodeficiency syndrome. Hum Pathol

low-dose diethylcarbamazine. Acta Paediatr 1993 ; 82 (1) : 116-118.

[245] Dodds EM. Toxoplasmosis. Curr Opin Ophthalmol 2006 ; 17 (6) : 557-561.

obstructive pneumonia. Thorax 1986 ; 41 (6) : 489-490.

838-840.

294-296.

2269-2274.

(5) : 473-478.

1994 ; 25 (7) : 652-658.

1991 ; 77 (8) : 697-702.

sis. Korean J Parasitol 2001 ; 39 (1) : 1-11.

nal pain in childhood. Br J Clin Pract 1992 ; 46 (4) : 271.

1987 ; 125 (6) : 1019-1034.


[234] Feldman GJ, Parker HW. Visceral larval migrans associated with the hypereosino‐ philic syndrome and the onset of severe asthma. Ann Intern Med 1992 ; 116 (10) : 838-840.

[222] Fernandez-Mestre MT, Layrisse Z, Montagnani S, Acquatella H, Catalioti F, Mastos M, *et al*. Influence of HLA class II polymorphism in chronic Chagas' disease. Parasite

[223] Colorado IA, Acquatella H, Catalioti F, Fernandez MT, Layrisse Z. HLA class IIDRB1, DQB11, DPB1 polymorphism and cardiomyopathy due to Trypanosoma cru‐

[224] Layrisse Z, Fernandez MT, Montagnani S, Mastos M, Balbas O, Herrera F, *et al*. HLA-C\*03 is a risk factor for cardiomyopathy in Chagas' disease. Hum Immunol 2000 ; 61

[225] Sierp GM, Albert ED, analysis of the HLA data. In : Gorodezky C, Sierp GM, Alberts E. (eds.) Immunogenetics Laboratory 1992 : Proceedings of the 5th Latin American

[226] del Puerto F, Nisshizawa JE, Kikuchi M, Roca Y, Avilas C, Gianella A, *et al*. Protective human leukocyte antigen haplotype, HLA-DRB1\*01-B\*14, against chronic Chagas'

[227] Borra′s SG, Diez C, Cotorruelo C, *et al*. HLA class II DRB1 polymorphism in Argenti‐ nians undergoing chronic trypanosome cruzi infection. Ann Clin Biochem 2006 ; 43

[228] Borrs SG, Racca L, Cotorruelo C, Biondi C, Beloscar J, Racca A. Distribution of HLA-DRB1 alleles in Artgentinean patients with Chagas' disease cardiomyopathy. Immu‐

[229] Pe′pin J, Khonde N, Maiso F, Doua F, Jaffar S, Ngampo S, *et al*. Short-course eflorni‐ thine in Gambian trypanosomiasis : a multicentre randomized controlled trial. Bull

[230] Fairlamb AH. Future prospects for chemotherapy of human trypanosomiasis 1. Nov‐ el approaches to the chemotherapy of trypanosomiasis. Trans R Soc Trop Med Hyg

[231] Jennings FW. Future prospects for the chemotherapy of human trypanosomiasis : combination therapy and African trypanosomiasis. Trans R Soc Trop Med Hyg 1990 ;

[232] Paiva CN, Feijo′ DF, Dutra FF, Carneiro VC, Freitas GB, Alves LS, *et al*. Oxidative stress fuels Trypanosoma cruzi infection in mice. J Clin Invest 2012 ; 122 (7) :

[233] Science Alerts Social Network. Factors affecting disease manifestation in humans : genetics and environment. http://sciencealerts.com/stories/2234502/Factors\_affect‐

ing\_disease\_manifestation\_of\_to... (accessed 3 January 2014).

disease in Bolivia. PLoS Negl Trop Dis 2012 ; 6 (3) : Article e1587.

zi chronic infection. Hum Immunol 2000 ; 61 (3) : 320-325.

Immunol 1998 ; 20 (4) : 197-203.

Histocompatibility Workshop.

nol Invest 2009 ; 38 (3-4) : 268-275.

World Health Organ 2000 ; 78 (11) : 1284-1295.

(9) : 925-929.

366 HLA and Associated Important Diseases

(Pt 3) : 214-216.

1990 ; 84 (5) : 613-617.

84 (5) : 618-621.

2531-2542.


[248] Elsevier, Inc. Toxoplasmosis causes, diagnosis and treatment-clinical key. https:// www.clinicalkey.com/topics/infectious-disease/toxoplasmosis.html (accessed 7 Janu‐ ary 2014).

late with disease severity and the infecting viral serotype in ethnic Thais. Tissue An‐

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

369

[263] LaFleur C, Granados J, Vargas-Alarcon G, Ruiz-Morales J, Villarreal-Garza C, Hiqu‐ eral L, *et al*. HLA-DR antigen frequencies in Mexican patients with dengue virus in‐ fection : HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic

[264] Loke H, Bethell DB, Phuong CX, Dung M, Schneider J, White NJ, *et al*. Strong HLA class I- restricted T-cell responses in dengue hemorrhagic fever : a double-edged

[265] Sakuntabhai A, Turbpaiboon C, Casade′mont I, Chuansumrit A, Lowhoo T, Kajaste-Rudnitski A, *et al*. A variant in CD209 promoter is associated with severity of dengue

[266] Fernandez-Mastre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNFα-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue

[267] Kalayanarooj S, Gibbons RV, Vaughn D, Green S, Nisalak A, Jarman RG, *et al*. Blood group AB is associated with increased risk for severe dengue disease in secondary

[268] Rico-Hesse R. Molecular evolution and distribution of dengue viruses type 1 and 2 in

[269] Rico-Hesse R, Harrison LM, Salas RA, Tovar D, Nisalak A, Ramos C, *et al*. Origins of dengue type 2 viruses associated with increased pathogenicity in the Americas. Vi‐

[270] Rodriguez-Roche RM, Alvarez M, Gritsun T, Halstead S, Kouri G, Gould EA, *et al*. Virus evolution during a severe dengue epidemic in Cuba, 1997. Virology 2005 ; 334

[271] Guzma′n MG, Kouri G, Bravo J, Valdes L, Vazquez S, Halstead SB. Effect of age on outcome of secondary dengue 2 infections. Int J Infect Dis 2002 ; 6 (2) : 118-124.

[272] Cologna R, Rico-Hesse R. American genotype structures decrease dengue virus out‐ put from human monocytes and dendritic cells. J Virol 2003 ; 77 (7) : 3929-3938.

[273] Leitmeyer KC, Vaughn DW, Watts DM, Salas R, Villalobos I, de Chacon, *et al*. Den‐ gue virus structural differences that correlate with pathogenesis. J Virol 1999 ; 73 (6) :

[274] Jessie K, Fong MY, Devi S, Lam SK, Wong KT. Localization of dengue virus in natu‐ rally infected human tissues, immunohistochemistry and in situ hybridization. J In‐

tigens 2002 ; 60 (4) : 309-318.

fever. Hum Immunol 2002 ; 63 (11) : 1039-1044.

sword ? J Infect Dis 2002 ; 184 (11) : 1369-1373.

disease. Nature Genet 2005 ; 37 (5) : 507-513.

fever patients. Tissue Antigens 2004 ; 64 (4) : 469-472.

infections. J Infect Dis 2007 ; 195 (7) : 1014-1017.

nature. Virology 1990 ; 174 (2) : 479-493.

rology 1997; 230 (2) : 244-251.

fect Dis 2004 ; 189 (8) : 1411-1418.

(2) : 154-159.

4738-4747.


late with disease severity and the infecting viral serotype in ethnic Thais. Tissue An‐ tigens 2002 ; 60 (4) : 309-318.

[263] LaFleur C, Granados J, Vargas-Alarcon G, Ruiz-Morales J, Villarreal-Garza C, Hiqu‐ eral L, *et al*. HLA-DR antigen frequencies in Mexican patients with dengue virus in‐ fection : HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum Immunol 2002 ; 63 (11) : 1039-1044.

[248] Elsevier, Inc. Toxoplasmosis causes, diagnosis and treatment-clinical key. https:// www.clinicalkey.com/topics/infectious-disease/toxoplasmosis.html (accessed 7 Janu‐

[249] Mack DG, Johnson JJ, Roberts F, Roberts CW, Estes RG, David C, *et al*. HLA-class II genes modify outcome of Toxoplasma gondii infection. Int J Parasitol 1999 ; 29 (9) :

[250] Laibe S, Ranque S, Curtillet C, Faraut F, Dumon H, Franck J. Timely diagnosis of dis‐ seminated toxoplasmosis by sputum examination. J Clin Microbiol 2006 ; 44 (2) :

[251] Petersen E, Edvinsson B, Lundgren B, Benfield T, Evengard B. Diagnosis of pulmona‐ ry infection with Toxoplasma gondii in immunocompromised HIV-positive patients

[252] Martina BEE, Koraka P, Osterhaus ADM. Dengue virus pathogenesis : an integrated

[253] Guha-Sapir D, Schimmer B. Dengue fever : new paradigms for a changing epidemi‐

[254] Guzman MG, Kouri G. Dengue and dengue hemorrhagic fever in the Americas : les‐

[256] Ong A, Sandar M, Chen MI, Sin LY. Fatal dengue hemorrhagic fever in adults during

[257] Guzma′n MG, Kouri G, Valdes L, Bravo L, Alvalez M, Vazques S, *et al*. Epidemiolog‐ ic studies on dengue in Santiago de Cuba, 1997. Am J Epidemiol 2000 ; 152 (9) :

[258] UNICEF, UNDP, World Bank, WHO. Evaluating diagnostics-Dengue : a continuing global threat. http://www.nature.com/reviews/micro (accessed 8 January 2014).

[259] Kouri GP, Guzma′n MG, Bravo JR. Why dengue hemorrhagic fever in Cuba? 2. An

[260] Halstead SB, Nimanitaya S, Cohen SN. Observations related to pathogenesis of den‐ gue hemorrhagic fever : Relation of disease severity to antibody response and virus

[261] Lee MS, Hwang KP, Chen TC, Lu PL, Chen TP. Clinical characteristics of dengue and dengue hemorrhagic fever in a medical center of southern Taiwan during the 2002

[262] Stephens HA, Klaythong R, Sirikong M, Vaughn DW, Green S, Kalayanarooj S, *et al*. HLA-A and HLA-B allele associations with secondary dengue virus infections corre‐

a dengue epidemic in Singapore. In J Infect Dis 2007 ; 11 (3) : 263-267.

integral analysis. Trans R Soc Trop Med Hyg 1987 ; 81 (5) : 821-823.

by real-time PCR. Eur J Clin Microbiol Infect Dis 2006 ; 25 (6) : 401-404.

view. Clin Microbiol Rev 2009 ; 22 (4) : 564-581.

ology. Emerg Themes Epidemiol 2005 ; 2 (1) : 1.

sons and challenges. J Clin Virol 2003 ; 27 (1) : 1-13.

[255] Halstead SB. Dengue. Lancet 2007 ; 370 (9599) : 1644-1652.

recovered. Yale J Biol Med 1970 ; 42 (5) : 311-328.

epidemic. J Microbiol Immunol Infect 2006 ; 39 (2) : 121-129.

ary 2014).

368 HLA and Associated Important Diseases

1351-1358.

646-648.

793-799.


[275] Paes MV, Pinhao AT, Barreto DF, Costa SM, Oliveira MP, Nogueira AC, *et al.* Liver injury and viremia in mice infected with dengue-2 virus. Virology 2005 ; 338 (2) : 236-246.

[288] Rasmuson J, Pourazar J, Linderholm M, Sandstrǒm T, Blomberg A, Ahlm C. Pres‐ ence of activated airway T lymphocytes in human Puumala hantavirus disease.

Influence of Human Leukocyte Antigen on Susceptibility of Tropical Pulmonary Infectious Diseases…

http://dx.doi.org/10.5772/58288

371

[289] Guirakhoo F, Kitchener S, Morrison D, Forrat R, McCarthy K, Nicholas R, *et al*. Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax-DEN2) vaccine : Phase I clinical trial for safety and immunogenicity : effect of yellow fever pre-immunity in induction of cross neutralizing antibody responses to all 4 dengue serotypes. Hum

[290] Durbin AP, Whitehead SS, McArthur J, Perreault JR, Blaney JE Jr, Thumar B, *et al*. rDEN4 Delta 30, a live attenuated dengue virus type 4 vaccine candidate, is safe, im‐ munogenic, and highly infectious in healthy adult volunteers. J Infect Dis 2005 ; 191

[291] Raviprakash K, Apt D, Brinkman A, Skinner C, Yang S, Dawes G, *et al*. A chimeric tetravalent dengue DNA vaccine elicits neutralizing antibody to all four virus sero‐

[292] Hermida L, Bernardo L, Martin J, Alvarez M, Prado I, Lo′ C, *et al*. A recombinant fu‐ sion protein containing the domain III of the dengue-2 envelope protein is immuno‐ genic and protective in nonhuman primates. Vaccine 2006 ; 24 (16) : 3165-3171. [293] Whitehead SS, Falqout B, Hanley KA, Blaney Jr JE Jr, Markoff L, Murphy BR. A live, attenuated dengue virus type 1 vaccine candidate with a 30-nucleotide deletion in the 3′ untranslated region is highly attenuated and immunogenic in monkeys. J Virol

[294] Edelman R, Wasserman SS, Bodison SA, Putnak RJ, Eckels KH, Tang D, *et al*. Phase I trial of 16 formulations of a tetravalent live-attenuated dengue vaccine. Am J Trop

[295] Ko AI, Goarant C, Picardeau M. Leptospira : The Dawn of the molecular genetics era for an emerging zoonotic pathogen. Nat Rev Microbiol 2009 ; 7 (10) : 736-747.

[296] Lingappa J, Kuffner T, Tappero J, Whitworth W, Mize A, Kaiser R, *et al*. HLA-DQ\*6 and ingestion of contaminated water : possible gene-environment interaction in an

[297] WHO recommended standards and strategies for surveillance, prevention and con‐ trol of communicable diseases, 2nd ed. http://www.who.int/emc (accessed 29 January

[298] Tubiana S, Mikulski M, Becam J, Lacassin F, Lefe`vre P, Gourinat AC. Risk factors and predictors of severe leptospirosis in New Caledonia. PLoS Negl Trop Dis 2013 ; 7

[299] Suputtamongkol Y, Pongtavornpinyo W, Lubell Y, Suttinont C, Hoontrakul S, Phim‐ da K, *et al.* Strategies for diagnosis and treatment of suspected leptospirosis : a cost-

outbreak of leptospirosis. Genes and Immun 2004 ; 5 (3) : 197-202.

types in rhesus macaques. Virology 2006 ; 353 (1) : 166-173.

Chest 2011 ; 140 (3) :715-722.

Vaccine 2006 ; 2 (2) : 60-67.

2003 ; 77 (2) : 1653-1657.

2014).

Med Hyg 2003 ; 69 (6 Suppl) : 48-60.

(1) : e1991. DOI : 10.1371/journal.pntd.0001991

(5) : 710-718.


[288] Rasmuson J, Pourazar J, Linderholm M, Sandstrǒm T, Blomberg A, Ahlm C. Pres‐ ence of activated airway T lymphocytes in human Puumala hantavirus disease. Chest 2011 ; 140 (3) :715-722.

[275] Paes MV, Pinhao AT, Barreto DF, Costa SM, Oliveira MP, Nogueira AC, *et al.* Liver injury and viremia in mice infected with dengue-2 virus. Virology 2005 ; 338 (2) :

[276] Seneviratne SL, Malavige GN, de Silva HJ. Pathogenesis of liver involvement during dengue viral infections. Trans R Soc Trop Med Hyg 2006 ; 100 (7) : 608-614.

[277] Nkhoma ET, Poole C, Vannappagari V, Hall SA, Beutler E. The global prevalence of glucose- 6-phosphate dehydrogenase deficiency : a systematic review and meta-anal‐

[278] Wu YH, Tseng CP, Cheng ML, Ho HY, Shih SR, Chiu DT. Glucose-6-phosphate de‐ hydrogenase deficiency enhances human coronavirus 229E infection. J Infect Dis

[279] Zivna I, Green S, Vaughn DW, Kalayanarooj S, Stephens HA, Chandanayingyong D, *et al*. T-cell responses to an HLA-B\*07-restricted epitope on the dengue NS3 protein

[280] Polizel JR, Bueno D, Visentainer JE, Sell AM, Borelli SD, Tsuneto LT, *et al*. Associa‐ tion of human leukocyte antigen DQ1 and dengue fever in a white Southern Brazil‐

[281] Alagarasu K, Mulay AP, Sarikhani M, Rashmika D, Shah PS, Celilia D. Profile of hu‐ man leukocyte antigen class I alleles in patients with dengue infection from Western

[282] Malavige GN, Fernando S, Fernando DJ, Seneviratne SL. Dengue viral infection.

[283] Likitnukul S, Prappal N, Pongpunlert W, Kingwatanakul P, Poovorawan Y. Dual in‐ fections : degue hemorrhagic fever with unusual manifestations and mycoplasma pneumonia in a child. Southeast Asian J Trop Med Public Health 2004 ; 35 (2) :

[284] Ali F, Saleem T, Khalid U, Mehwood SF, Jamil B. Crimen-Congo hemorrhagic fever in a dengue-endemic region : lessons for the future. J Infect Dev Ctries 2010 ; 4 (7) :

[285] Duchin JS, Koster FT, Peters CJ, Simpson GL, Tempest B, Zaki SR, *et al*. The Hantavi‐ rus Study Group. Hantavirus pulmonary syndrome : a clinical description of 17 pa‐

tients with a newly recognized disease. N Engl J Med 1994 ; 330 (14) : 949-955.

[286] Castillo C, Naranjo J, Sepu′lveda A, Ossa G, Levy H. Hantavirus pulmonary syn‐ drome due to Andes virus in Temuco, Chile : clinical experience with 16 adults.

[287] Vapalahti O, Mustonen J, Lundkvist A, Henttonen H, Plyusnin A, Vaheri A. Hantavi‐

rus infections in Europe. Lancet Infect Dis 2003 ; 3 (10) : 653-661.

correlate with disease severity. J Immunol 2002 ; 168 (11) : 5959-5965.

ian population. Mem Inst Oswaldo Cruz 2004 ; 99 (6) : 559-562.

ysis. Blood Cells Mol Dis 2009 ; 42 (3) : 267-278.

India. Hum Immunol 2013 ; 74 (12) : 1624-1628.

Postgrad Med J 2004 ; 80 (948) : 588-601.

236-246.

370 HLA and Associated Important Diseases

399-402.

459-463.

Chest 2001 ; 120 (2) : 548-554.

2008 ; 197 (6) : 812-816.


benefit analysis. PLoS Negl Trop Dis 2010 ; 4 (2) : e610. DOI : 10.1371/journal.pntd. 0000610


benefit analysis. PLoS Negl Trop Dis 2010 ; 4 (2) : e610. DOI : 10.1371/journal.pntd.

[300] Nitipan S, Sritrakul T, Kunjantarachot A, Prapong S. Identification of epitopes in Leptospirosis borgpetersenii leucine-rich repeat proteins. Infect Genet Evol 2013 ; 14

[301] Umamaheswari A, Pradhan D, Hemanthkumar M. Computered aided subunit vac‐ cine design against pathogenic Leptospira serovars. Interdiscip Sci 2012 ; 4 (1) : 38-45.

(NA) : 46-57. DOI : 10.1016/j.meegid.2012.10.014.

0000610

372 HLA and Associated Important Diseases

## *Edited by Yongzhi Xi*

This year marks the 60th anniversary of HLA discovery by the French Nobel laureate physician Jean Dausset, as well as the 55th anniversary of the identification and naming of the first HLA. Under such circumstances, both basic HLA research and its clinical applications need a new book that comprehensively reflects the latest achievements in the field. Thus, Professor Xi as Editor has contributed to organize international experts in the areas of HLA-related basic research and clinical applications, to unite their knowledge in chapters covering various related topics, and finally to finish the book "HLA and Associated Important Diseases". The book consists of three sections which mainly include basic theoretical and technological developments, several important HLA-associated autoimmune diseases and HLAassociated infectious diseases.

Photo by BravissimoS / iStock

HLA and Associated Important Diseases

HLA and Associated

Important Diseases