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(Circulation. 1998;97:1124-1128.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Association of High-Altitude Pulmonary Edema With the Major Histocompatibility Complex

Masayuki Hanaoka, MD; Keishi Kubo, MD; Yoshitaka Yamazaki, MD; Takashige Miyahara, MD; Yukinori Matsuzawa, MD; Toshio Kobayashi, MD; Morie Sekiguchi, MD; Masao Ota, PhD; ; Hideto Watanabe, MD

From the First Department of Medicine (M.H., K.K., Y.Y., T.M., Y.M., T.K., M.S.) and Department of Legal Medicine (M.O.), Shinshu University School of Medicine, Matsumoto, Japan, and Toyama Citizen Hospital (H.W.), Toyama, Japan.

Correspondence to Keishi Kubo, MD, First Department of Medicine, Shinshu University School of Medicine, 3–1-1 Asahi, Matsumoto, 390 Japan.

	Abstract

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Background—A constitutional susceptibility has been suggested in the development of high-altitude pulmonary edema (HAPE) because HAPE generally affects healthy young people, some of whom suffer recurrent episodes. We examined whether immunogenetic susceptibility is present in HAPE-susceptible subjects.

Methods and Results—The frequencies of human leukocyte antigen (HLA) alleles in 28 male and 2 female subjects with a history of HAPE were compared with those in 100 healthy volunteers. We assayed the HLA-A, -B, -C, -DR, and -DQ antigens serologically. The pulmonary hemodynamics on admission to the hospital and the ventilatory response to hypoxia and hypercapnia were retrospectively examined in 10 of the HAPE-susceptible subjects. HLA-DR6 was positive in 14 (46.7%) of the subjects with HAPE but only 16.0% of the control subjects (P=.0005), and HLA-DQ4 was positive in 12 (40.0%) of the subjects with HAPE but only 10.0% of the control subjects (P=.0001). HLA-DR6 or HLA-DQ4 was positive in 8 (100%) of the subjects with recurrent HAPE. The pulmonary arterial pressure on admission of the HLA-DR6–positive subjects with HAPE was significantly higher than that of the HLA-DR6–negative subjects with HAPE.

Conclusions—There were significant associations of HAPE with HLA-DR6 and HLA-DQ4 and of pulmonary hypertension with HLA-DR6. An immunogenetic susceptibility, which is associated with HLA class II alleles located within the major histocompatibility complex, may underlie the development of HAPE, at least in some of its forms.

Key Words: edema • genetics • hemodynamics • hypertension, pulmonary • ventilation

	Introduction

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Some mountain climbers who have no past history of any cardiopulmonary problems experience HAPE, a severe form of acute mountain sickness, after rapid ascent to altitudes in excess of 2700 m above sea level.^{1 2 3 4} This form of noncardiogenic pulmonary edema is rare and is sometimes complicated with cerebral edema or retinal hemorrhage. A few cases of HAPE are reported every year in Japan, and some of these patients are transported to our institution, Shinshu University Hospital (610 m above sea level), or Toyama Citizen Hospital (10 m above sea level) from the "Japan Alps" of the central area of Japan.⁵ HAPE generally affects healthy young people, some of whom suffer recurrent episodes.^{6 7} It often occurs at moderate altitudes in Japan. For these reasons, it has been speculated that a constitutional susceptibility underlies the development of this disease. We observed 51 cases of HAPE from November 1971 to September 1996, and 10 (19.6%) were recurrent episodes. These findings appear to support the previous observation that individuals who have developed HAPE are more likely to experience future episodes than the general population.

In contrast, a striking genetic association has been reported between certain HLA alleles and susceptibility to some diseases. To examine whether immunogenetic susceptibility is present in HAPE-susceptible subjects, we performed HLA typing for A, B, C, DR, and DQ alleles in subjects with a history of HAPE and compared the results with those of healthy subjects who were chosen at random throughout Japan. Moreover, we retrospectively examined the pulmonary hemodynamics on admission to the hospital and the ventilatory response to hypoxia and hypercapnia in some HAPE-susceptible subjects to see whether HLA alleles might be related to these physiological parameters.

	Methods

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Subjects
We examined 30 subjects with histories of HAPE and 100 control subjects. All subjects were healthy adult natives of Japan, and none were taking any medication. All subjects gave informed consent.

The subjects with histories of HAPE consisted of 28 males and 2 females, ranging in age from 15 to 75 years with an average age of 30.0 years (Table 1). They had all been born and resided at low altitude (<610 m) and had experienced at least one episode of HAPE requiring hospitalization while climbing in the Japan Alps. Eight (26.7%) of them had had recurrent episodes. The altitude at the onset of HAPE ranged from 2857 to 3190 m above sea level. We diagnosed HAPE on the basis of the following criteria⁸ : onset at high altitude of the typical symptoms, including cough and dyspnea at rest; absence of infection; presence of pulmonary rales and cyanosis; disappearance of symptoms and signs within 3 days of the start of treatment with bed rest and supplemental oxygen; and chest roentgenographic infiltrates consistent with pulmonary edema. All subjects with HAPE met all criteria at the onset of the disorder and recovered promptly and well with hospitalization. They were all in good health at the time of the present study.

View this table: [in this window] [in a new window]   Table 1. Age, Sex, Symptoms, and Blood Gas Values During HAPE in Each of the 30 Subjects With HAPE

The control subjects had all been born and resided at altitudes <610 m in Japan; they had no history of cardiopulmonary diseases.

Measurements
HLA Typing
Venous blood samples were obtained from the patients and control subjects. Lymphocytes were isolated from peripheral blood by use of a density gradient centrifugation technique,⁹ and B cells were separated with Lympho-Kwik reagent (One Lambda). The mononuclear cells were subjected to HLA-A, -B, and -C typing with a standard microcytotoxicity test,¹⁰ whereas HLA-DR and HLA-DQ typing was performed on the B cells by use of a similar technique but with prolonged incubation times.¹¹

Pulmonary Hemodynamics
Of the 30 subjects with HAPE, 10 (9 male subjects and 1 female subject) had undergone pulmonary hemodynamic studies. Right cardiac catheterization during room air breathing was performed within 6 hours after admission to Shinshu University Hospital. A thermodilution Swan-Ganz catheter was introduced percutaneously into the pulmonary artery via the right internal jugular vein. The pulmonary arterial pressure and pulmonary arterial wedge pressure were measured on a transducer system with the use of a calibrated pressure transducer (Statham P50), and cardiac output was measured by the thermodilution method with the use of a cardiac computer (Edwards 9520A). We calculated pulmonary vascular resistance by subtracting pulmonary arterial wedge pressure from pulmonary arterial pressure and dividing by the cardiac output.

Ventilatory Responses
After complete recovery, ventilatory responses were also measured in the same 10 subjects with HAPE with the use of a rebreathing system. Ventilatory responses were assessed by use of the progressive isocapnic HVR described by Weil et al¹² and the HCVR described by Read.¹³ We evaluated the HVR using the slope of linear regression between VE and SaO₂. This slope is termed VE/SaO₂. A high slope value indicates a brisk ventilatory response to hypoxia. HCVR was analyzed from the equation VE=S(P_ETCO₂-B), where S is the slope of the line derived from plotting VE versus end-tidal CO₂ partial pressure (P_ETCO₂) and B is the extrapolated intercept of the P_ETCO₂ axis.¹³ Values were measured after an equilibration period. A high slope value also indicates a brisk ventilatory response to hypercapnia. All studies were conducted at Shinshu University Hospital.

Statistical Analysis
HLA data were analyzed by the standard statistical procedure of ² contingency table analysis and Fisher's exact test. The OR was provided by the cross-product ratio (incidence ratio) of the entries in the 2x2 table (ie, ad/bc). Data for pulmonary hemodynamics and ventilatory responses are expressed as mean±SEM. Comparison of data between the subgroups of HAPE-susceptible subjects was made by use of the Student's t test. A value of P<.05 was considered significant.

	Results

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HLA Typing
The frequencies for the HLA class II alleles in the subjects with HAPE and the control subjects are shown in Table 2. HLA-DR6 and -DQ4 were significantly more frequent in the subjects with HAPE than in the control subjects. DR6 was positive in 14 (46.7%) of the subjects with HAPE but in only 16.0% of the control subjects (P=.0005, OR=4.6). DQ4 was positive in 12 (40.0%) of the subjects with HAPE but only 10.0% of the control subjects (P=.0001, OR=6.0). In 4 of the subjects with HAPE, both DR6 and DQ4 were positive. There was also a significant difference for HLA-B44 (26.7% of HAPE subjects versus 11.0% of the control subjects; P=.042, OR=2.9). In the HAPE subjects, the B44 allele was frequently expressed; however, the increase of the B44 antigen frequency was consistent with the linkage disequilibrium of B44 and DR6 in Japanese individuals. For other HLA types, there was no significant difference in frequency between the two groups.

View this table: [in this window] [in a new window]   Table 2. Frequency of HLA-DR and -DQ Antigens in Subjects With HAPE and Control Subjects

HAPE recurrence was shown in all 8 of the HLA-DR6–or HLA-DQ4–positive subjects. Six (42.9%) of the 14 DR6-positive subjects experienced recurrent episodes versus only 2 (12.5%) of 16 DR6-negative subjects.

Pulmonary Hemodynamics
Pulmonary hemodynamics on admission were examined separately in the DR6-positive (n=5) and DR6-negative (n=5) subjects. In both subgroups, pulmonary hemodynamic data (Table 3) demonstrated normal pulmonary arterial wedge pressure, normal cardiac output, and increased pulmonary vascular resistance. The pulmonary arterial pressure, however, was significantly increased in the DR6-positive subgroup (P<.05).

View this table: [in this window] [in a new window]   Table 3. Pulmonary Hemodynamics and Ventilatory Responses in Subjects With HAPE

Ventilatory Responses
Ventilatory responses were also examined separately in the two subgroups (n=5 each). There were no significant differences between the subgroups in either HVR or HCVR (Table 3).

	Discussion

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The most noteworthy immunogenetic findings in the 30 subjects with HAPE were the increased frequencies of HLA-DR6 and HLA-DQ4 compared with those in the control subjects. HAPE occurred recurrently in all 8 subjects who had either HLA-DR6 or HLA-DQ4 and in 6 of the 14 DR6-positive subjects. Furthermore, the HLA-DR6–positive patients with HAPE showed a significant increase in pulmonary arterial pressure on admission compared with the HLA-DR6–negative patients with HAPE.

Many investigators have pointed out the possibility of a constitutional susceptibility to HAPE.^{7 8} Individual susceptibility may be associated with enhanced pulmonary vascular reactivity to hypoxia and exercise. We found that HAPE-susceptible subjects showed a much greater increase in pulmonary vascular resistance than control subjects, resulting in a much higher level of pulmonary arterial pressure, under both acute hypoxia of 15% oxygen and acute hypobaria of 515 mm Hg.¹⁴ Moreover, HAPE-susceptible subjects exhibited a tendency toward increased pulmonary vascular resistance even during normoxic light exercise with a supine bicycle ergometer, therefore showing a greater increase in pulmonary arterial pressure and greater decrease in arterial oxygen tension during exercise under both conditions. Similar observations were described by Hultgren et al¹⁵ and Fasules et al.¹⁶ Hultgren et al¹⁵ studied HAPE-susceptible subjects both at sea level and 24 hours after ascent to an altitude of 3100 m. Although none developed clinical or radiographic evidence of pulmonary edema, all developed marked pulmonary hypertension and hypoxemia. Fasules et al¹⁶ found that HAPE-susceptible children had greater pulmonary arterial pressure than did nonsusceptible children with acute hypoxia of 16% oxygen.

It has been indicated that pulmonary hypertension plays an important role in the initiation and development of HAPE, although pulmonary hypertension itself does not cause pulmonary edema. The high pulmonary arterial pressure found in HAPE patients must play a role in the mechanism of the condition, because the prophylactic administration of nifedipine was effective in lowering pulmonary artery pressure and preventing HAPE in susceptible subjects.¹⁷ The inhalation of NO also produced a decrease in systolic pulmonary artery pressure and improved arterial oxygenation in HAPE-susceptible subjects.¹⁸ West and Mathieu-Costello^{19 20} proposed that HAPE was caused by damage to the walls of pulmonary capillaries as a result of very high wall stress associated with increased capillary transmural pressures that were the result of uneven hypoxic pulmonary vasoconstriction. In the present study, there was significantly increased pulmonary arterial pressure in the HLA-DR6–positive HAPE patients breathing room air on admission to the hospital compared with the HLA-DR6–negative patients. Pulmonary vascular resistance also tended to be increased in this group. We consider that one of the mechanisms contributing to HAPE is pulmonary hypertension, which is caused by an increase in pulmonary vascular resistance resulting from either microvascular injury or obstruction. The results of the present study indicate that HLA-DR6 may be related to pulmonary hypertension.

Recently, it was found that the primary pulmonary hypertension in HIV infection was associated with HLA-DR6 and HLA-DR52.²¹ HIV-associated primary pulmonary hypertension may reflect a host response to HIV-1 determined by one or more HLA-DR alleles located within the major histocompatibility complex. Moreover, the presence of HLA-DR6 and HLA-DR52 was associated with significantly increased risk of a fatal disease outcome with pulmonary hypertension in scleroderma.²² The expression of pulmonary hypertension appears to require an environmental trigger or additional genes. Multiple heterogeneous immunologic events also play a role in the development of pulmonary hypertension.²³ The possible routes include vasculitis with immune complex deposition, the induction of activation molecules such as HLA class II on endothelial cells with inflammatory infiltrates, and release of cytokines and mediators (T-cell–mediated vascular injury) and initiation of noninflammatory vasculopathy via procoagulant activity (recurrent thromboembolism, thrombosis in situ, or both). The release of inflammatory cytokines and vasoconstricting mediators could follow any of these pathways.²³ We²⁴ recently reported that endothelin-1 is a vasoconstrictor that contributed to the pulmonary hypertension in HAPE. We also showed that there were significant increases in the levels of total cells (especially macrophages and neutrophils), total protein, albumin, IL-1, IL-6, IL-8, and tumor necrosis factor- in bronchoalveolar lavage fluid in patients with HAPE compared with the values after recovery, suggesting that an inflammatory process may occur in HAPE.²⁵ It is believed that an inflammatory process resulting from immunologic events, triggered and enhanced by environmental factors, may lead to pulmonary hypertension resulting in HAPE.

The pathogenesis of HAPE is multifactorial. Various mechanisms take part in the initiation of the condition and its progression. We postulate that both immunologic events and inflammatory processes are important in the development of HAPE, which occurs at moderate altitudes and affects young people recurrently. The clinical evidence linking HAPE to inflammatory processes is that the onset of HAPE occurred 48 to 96 hours from the beginning of ascent⁵ and that acute hypoxia did not cause pulmonary edema in HAPE-susceptible subjects in previous studies.^{14 15 16} A period of 48 to 96 hours may be sufficient for the inflammatory process to progress to the point of the initiation of HAPE. Moreover, dexamethasone, an effective immunosuppressive agent, has been successfully used to prevent and treat acute mountain sickness.²⁶

It is clear, at least, that HAPE occurs in relationship to both environmental and individual factors. The environmental factors are unique to high altitude and include hypoxia, hypobaria, and low temperatures. The individual factors include susceptibility to hypoxia, hypobaria, or exercise, each of which enhances pulmonary hypertension, and associated conditions experienced during a period at high altitude, such as upper respiratory infection. One of the possible explanations for the pathogenesis of HAPE is that an initial event, such as upper respiratory infection, may induce a host response to the environmental factors associated with HLA class II alleles, then an inflammatory process may occur and lead to pulmonary hypertension resulting in HAPE. Actually, Fasules et al¹⁶ suggested that upper respiratory infections may play a role in the pathogenesis of HAPE.

In summary, increased frequencies of HLA-DR6 and HLA-DQ4 in subjects with HAPE were demonstrated. All eight subjects with recurrent episodes of HAPE had either HLA-DR6 or HLA-DQ4. HLA-DR6–positive patients with HAPE showed a significant increase in pulmonary arterial pressure on admission. These findings suggest that susceptibility to HAPE is associated with major histocompatibility complex alleles, notably with HLA-DR6 or HLA-DQ4, either alone or in combination. We conclude that HLA class II alleles located within the major histocompatibility complex may contribute to the individual factors, ie, constitutional susceptibility, in the development of some types of HAPE.

	Selected Abbreviations and Acronyms

 

HAPE = high-altitude pulmonary edema HCVR = hyperoxic hypercapnic ventilatory response HLA = human leukocyte antigen HVR = hypoxic ventilatory response IL = interleukin OR = odds ratio SaO2 = arterial O2 saturation VE = minute ventilation

	Acknowledgments

 
The authors greatly appreciate the kind suggestions of Robert B. Schoene, MD, Professor of Medicine, Harborview Medical Center, Seattle, Wash, for our paper. They thank Drs R. Ge, D. Yunden, K. Fujimoto, T. Honda, T. Koizumi, S. Yoshikawa, S. Horie, M. Hayasaka, T. Hayano, K. Okada, T. Hachiya, H. Nomura, E. Sato, and S. Yamaguchi for their generous support of this study. They are also grateful to SRL Co (Tokyo, Japan) for technical assistance in the serological assay of HLA.

Received August 18, 1997; revision received November 3, 1997; accepted December 1, 1997.

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