The Impact of Infectious Diseases on the Health of U.S. Troops Deployed to the Persian Gulf During Operations Desert Shield/Desert Storm

Kenneth C. Hyams¹
Kevin Hanson²
F. Stephen Wignall³
Joel Escamilla⁴
Edward C. Oldfield III⁵

¹ Epidemiology Division, Naval Medical Research Institute, Bethesda, Maryland
² Office of the I Marine Expeditionary Force (MEF) Surgeon, I MEF, Camp Pendleton, California
³ U.S. Naval Medical Research Unit No. 2, Jakarta, Indonesia
⁴ Navy Environmental and Preventive Medicine Unit No. 6, Pearl Harbor, Hawaii
⁵ Division of Infectious Diseases, Eastern Virginia Medical School, Norfolk, Virginia

The opinions and assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the U.S. Department of Defense or the U.S. Department of the Navy.

Abstract

An assessment was conducted of the impact of infectious diseases on the 697,000 U.S. troops deployed to the Persian Gulf during 1990-1991 in Operations Desert Shield and Desert Storm. The incidence of nonbattle injuries, including infectious diseases, during this conflict was lower than during previous wars involving U.S. military personnel. The major reported causes of morbidity were generally mild cases of acute diarrheal and upper respiratory disease. The most unexpected outcome was the lack of arboviral infections, particularly sandfly fever, and the occurrence among U.S. troops of 12 cases of visceral leishmaniasis due to Leishmania tropica. The fact that infectious diseases were not a major cause of lost manpower, in sharp contrast to the experience among military personnel in World War II, can be attributed to a combination of factors: the presence of a comprehensive infrastructure of medical care, extensive preventive medicine efforts, and several fortuitous circumstances. Beneficial conditions that may not be present in future conflicts in this region include isolation of most combat troops to barren desert locations during the cooler, winter months, which provided the least favorable conditions for transmission of arthropod-borne diseases.

Introduction

Between August 1990 and March 1991, the United States deployed a total of 697,000 troops to the Persian Gulf during Operations Desert Shield (the buildup period) and Desert Storm (the 6-week war with Iraq). In contrast to previous wars, a higher percentage of deployed troops were reservists/National Guard personnel (17%) and women (7%).

Throughout this massive deployment, there was substantial concern that infectious diseases that are endemic in this area of the world could threaten the health of coalition troops [1,2]. On the basis of experience with infectious diseases among military personnel during World War II, foreign troops stationed in the Persian Gulf were expected to be at especially high risk of shigellosis, malaria, sandfly fever, and cutaneous leishmaniasis [3,4]. Epidemiologic surveillance of deployed troops and studies conducted during the 4 years since the war with Iraq have provided a better understanding of the threat of infectious diseases in the Persian Gulf and also help provide a guide for the diagnosis and treatment of ill Gulf war veterans.

An assessment was conducted of the impact of infectious diseases on U.S. troops by use of published reports and data derived from the U.S. Navy's weekly surveillance system of outpatient visits among approximately 40,000 Marine Corps ground troops deployed to northeastern Saudi Arabia. A MEDLINE search for relevant articles in any language was conducted with the following MESH headings: Operation Desert Shield, Operation Desert Storm, Gulf war, Persian Gulf, Middle East, Iraq, Kuwait, and Saudi Arabia. In addition, 594 citations were examined in a "Current Bibliographies in Medicine" prepared in March 1994 by the National Library of Medicine [5]. Applicable publications also were found by a comprehensive examination of the reference section of articles dealing with this topic.

Background

After Iraq invaded Kuwait on August 2, 1990, U.S. troops were rapidly transported to the theater of operations mostly by aircraft. On arrival, combat troops were crowded together in warehouses and tents at initial staging areas and then moved to isolated desert locations in northeastern Saudi Arabia (figure 1). Although most ground troops lived in tents, it was necessary to use a wide variety of buildings in military and guest worker camps to accommodate U.S. military personnel.

Food supplies had to be procured from numerous sources to meet the immediate needs of such a large force, and most troops ate prepackaged meals supplemented by fresh food obtained from nearby countries [6]. In contrast to the food supplies, potable water was obtained from only a few closely monitored sources, predominantly commercial bottled water and military reverse-osmosis units.

Military personnel were extremely busy and at high risk of injury and disease during Operations Desert Shield and Desert Storm; more than 500,000 troops were rushed into an inhospitable desert environment, readied equipment, conducted training exercises, and eventually fought a war [7]. The first 2 months of the deployment were particularly hazardous because the weather was extremely hot (mean high temperature of 107°F), and heat stress was a major health threat. However, by December and January when the majority of troops were deployed, the weather had become much cooler (mean high temperature, 72°F).

A comprehensive health care system was established by the U.S. military to provide for the medical demands expected in a prolonged war with massive casualties [8-10]. In addition, an extensive preventive medicine effort was initiated that included strict monitoring of the purity of potable water, inspection of food sources and supplies, maintenance of field camp sanitation, institution of an arthropod vector control program, and administration of booster doses of routine vaccinations (principally typhoid and tetanus), influenza vaccine during the fall, and immune serum globulin [10].

Besides these standard preventive medicine procedures, a continuous program of disease surveillance and a sophisticated laboratory for the diagnosis of infectious diseases were established in Saudi Arabia by the U.S. Navy at the beginning of Operation Desert Shield [11]. Because of these innovations, it was possible to monitor U.S. troops more closely than had been feasible previously. Outpatient morbidity data were collected from a population of approximately 40,000 U.S. Marine Corps combat troops in a weekly surveillance program, which provided risk assessment information that was most specific for U.S. ground troops deployed in northeastern Saudi Arabia.

Medical surveillance among the 40,000 U.S. Marines and hospitalization statistics indicated that the "disease nonbattle injury" rate, which includes infectious diseases, was lower during this military campaign than in any major war involving U.S. military personnel [3,12,13]. Furthermore, the incidence of nonbattle injuries steadily decreased during the deployment as weather conditions improved, troops adapted to the demands of the deployment, and disease surveillance efforts quickly identified major health hazards (figure 2). In addition to low morbidity rates, fewer deaths occurred among U.S. military personnel deployed in Operations Desert Shield and Desert Storm than initially anticipated: 148 killed in action and 226 noncombat deaths resulting primarily from accidental injuries [14,15]. No deaths due to infectious diseases were reported.

Although a high level of health and combat readiness was maintained among deployed troops, nondisabling acute enteric and respiratory infections were a frequent occurrence in the Persian Gulf.

Gastroenteritis

Diarrheal disease was the leading cause of infectious disease morbidity among U.S. troops [2,16]. At the beginning of the rapid buildup of troops in August-September 1990, when the weather was very hot, outbreaks of acute diarrhea were common. More than 50% of the troops in some initially deployed units reported an episode of acute diarrhea, as defined by three or more loose or watery stools in a 24-hour period [16]. Although acute diarrhea was a frequent complaint, the majority of troops experienced mild, traveler's-type diarrhea which resolved spontaneously after a few days [16].

The primary enteropathogens identified in cases of acute diarrhea from all branches of the military were enterotoxigenic Escherichia coli (ETEC) and Shigella sonnei (table 1) [16]. Other species of Shigella, non-typhi Salmonella, enteroinvasive E. coli, and Campylobacter were found much less often. No confirmed, acute case of cholera, typhoid fever, amoebic dysentery, or giardiasis was reported among U.S. troops. Also, examination of stool samples from 422 combat troops after the war did not find an increased risk of enteric protozoan or helminthic infections [17].

As expected from recent U.S. military deployments in this region [18,19], between 20% and 80% of bacterial enteropathogens were resistant to antibiotics commonly used to treat acute diarrhea, including trimethoprim-sulfamethoxazole, tetracycline, and ampicillin [16]. However, all isolated bacterial pathogens were found to be sensitive to quinolone drugs which became standard therapy for severe cases of acute diarrhea [20].

The wide diversity of colonization factor antigens, serotypes, plasmid profiles, and antibiograms among isolated strains of ETEC and Shigella species indicated that there were numerous sources of enteric pathogens [16,21]. Fresh, locally grown produce was the primary suspected source during early outbreaks [6,16], but the possibility that enteric pathogens were carried from the United States by a few, minimally symptomatic troops could not be ruled out.

The major risk factor for diarrheal disease among initially deployed ground troops was consumption of fresh fruits and vegetables obtained from neighboring countries, as demonstrated by the precipitous decrease in rates of diarrheal disease when these food items were identified as a risk factor and removed from the diet of the ground troops [16] (figure 3). After the initial outbreaks, diarrheal disease continued to occur at a lower and declining rate among ground troops; the major risk factor for transmission became deployment to field locations [16]. Once enteropathogens were introduced into populations of crowded ground troops who were living in tents without modern indoor plumbing, endemic transmission appeared to continue by close personal contact, contamination of communal latrines and washing facilities by troops with acute diarrhea, and possibly desert filth flies, which were a ubiquitous nuisance [22,23].

Other distinctive risk factors for transmission of diarrheal disease were identified in isolated outbreaks and cases of acute gastroenteritis and involved preparation of meals by foreign food handlers and use of locally catered meals [20,24]. For shipboard personnel, a major risk factor for diarrheal disease was eating in local restaurants while they were on shore leave [25].

Viral gastroenteritis also was a cause of morbidity among U.S. troops during both Operation Desert Shield and Operation Desert Storm [16,26]. Beginning in the cooler months of November and December 1990, outbreaks of Norwalk virus infection, characterized predominantly by vomiting, occurred in widely scattered ground units [16,27]. A serologic study of 404 Desert Storm troops indicated that up to 6% of some combat units may have been infected with Norwalk virus [26]. Affected troops generally had acute self-limited symptoms which lasted for 24-48 hours.

Respiratory Disease

Acute, common cold-type respiratory complaints were a widespread cause of minor morbidity during both Operation Desert Shield and Operation Desert Storm, especially during periods of initial deployment and crowding (figure 4) [25,28,29]. The British also reported an increase in community-acquired pneumonia during deployment among their 42,000 Desert Shield/Storm troops [30] and an outbreak of chicken pox in a military field hospital [31].

There was the additional concern that respiratory disease would result from exposure to the sand in this region which can be extremely fine and powdery [28,32]. Although ground troops were constantly exposed to blowing sand and sand suspended at ground level by the movement of troops and equipment, a survey of 2,598 U.S. troops indicated that upper respiratory symptoms, other than chronic rhinorrhea, were most common among the minority of troops who resided in air-conditioned buildings [28]. This finding suggests that troops living and working in tightly constructed buildings were more likely to transmit respiratory pathogens among themselves than troops living in the field in tents. Similar findings have been observed in U.S. military recruit camps where troops living in modern, energy-efficient barracks with closed ventilation systems are at higher risk of respiratory-transmitted infections [33].

Leishmaniasis

Because cutaneous leishmaniasis had been a problem for foreign troops stationed in Iran and Iraq during World War II [34], it was anticipated that U.S. ground troops would also be at risk. However, it was not anticipated that U.S. troops would be at risk of visceral leishmaniasis, which is not endemic to this area. Nor was it expected that Persian Gulf veterans infected with Leishmania tropica, which causes cutaneous disease, would present with visceral infection without the classic severe symptoms and signs of kala-azar [35-39]. Mildly symptomatic visceral L. tropica infection, named "viscerotropic leishmaniasis" [35], previously had not been described among Western guest workers or the local populations of Saudi Arabia, although there have been isolated reports of L. tropica causing visceral disease in Africa and Southwest Asia [40,41].

To date, 12 cases of visceral and 19 cases of cutaneous leishmania infection have been reported among U.S. Gulf war veterans who were deployed to Saudi Arabia, Kuwait, and southern Iraq [42]. L. tropica was found in cases of visceral disease and Leishmania major in cutaneous cases in which parasites could be cultured and evaluated by isoenzyme analysis [39].

Among the 12 U.S. veterans with visceral L. tropica infection, one was asymptomatic and the rest presented with various systemic signs of disease, predominantly fever, hepatosplenomegaly, and lymphadenopathy, but they did not have cutaneous manifestations [36]. Laboratory studies revealed very mild anemia and modest aminotransferase evaluations, but unlike patients with kala-azar, these patients usually have not had leukopenia, thrombocytopenia, or hypergammaglobulinemia [36]. Three of the veterans with visceral leishmaniasis also had other systemic diseases: HIV type 1 infection, renal cell carcinoma, and acute infection due to Epstein-Barr virus [36,38].

Evaluating Desert Storm veterans for visceral L. tropica infection has been difficult because there is no sensitive and specific serologic or skin screening test. All infections have had to be diagnosed by the identification of parasites in bone marrow or lymph node biopsy specimens by means of either culture or an indirect immunofluorescence assay, which are demanding procedures because this disease is characterized by a low parasite burden.

Although it has been difficult to diagnosis visceral L. tropica infection, no indication has been found of widespread leishmania transmission among the more than 40,000 U.S. troops who have been evaluated clinically in the Department of Veterans Affairs and Department of Defense Persian Gulf health registries [42]. In addition, all patients who had visceral leishmania infection except one have had objective signs of disease, which should be apparent if large numbers of troops were infected. The small number of cases of cutaneous leishmaniasis, which is more common in Saudi Arabia and easier to diagnose than visceral leishmaniasis, further suggests that leishmania infection was not widespread.

There are several possible reasons for a low number of cases of cutaneous and visceral leishmaniasis among U.S. troops. For one, insecticides and repellents were used against arthropod vectors in areas where ground troops were camped. Also, most combat troops were stationed in the open desert rather than in oases or urban areas where the sandfly vector and primary leishmania host, desert rodents, thrive [43-45]. Lastly, the time of the year when U.S. troops were deployed may have been critical [46]. In this region, sandflies are most active during the hot summer months [43,45]. Although the first U.S. troops were sent to Saudi Arabia on August 8, 1990, the peak of the buildup did not occur until the cooler winter season between December and February, and the majority of troops had returned to the U.S. by May 1991. Consequently, most troops were deployed during the lowest period of sandfly activity.

Other Arthropod-Borne Infections

At the beginning of Operation Desert Shield, sandfly fever was considered one of the most serious infectious disease threats to the combat readiness of U.S. troops because this viral infection had been a cause of widespread morbidity in Iran and Iraq during World War II [43]. Although not a cause of mortality, the high fever and intense debility caused by sandfly fever nevertheless can incapacitate large numbers of nonimmune troops for brief periods of time.

During Operations Desert Shield and Desert Storm, no outbreak of febrile disease consistent with sandfly fever or other arthropod-borne diseases was reported or observed in the U.S. Navy disease surveillance system of 40,000 Marine Corps personnel. Also, no evidence of this arboviral infection was found in serologic studies of 37 cases of acute fever unaccompanied by diarrhea among troops from widely varying units [47] and in a serosurvey of 865 ground troops who were evaluated predeployment and postdeployment [48].

The reasons why U.S. troops were at low risk of sandfly fever may be related to the low number of cases of leishmaniasis because these two diseases are transmitted by the same sandfly vector. Use of insecticides and limited sandfly activity during the cold winter months when most troops were deployed would have lessened the risk of transmission of both diseases [45,46]. Furthermore, because of differences in geographic location, the risk of sandfly fever may not have been as great for Desert Storm troops who were deployed in the open deserts of Saudi Arabia as for World War II soldiers who were stationed further north in the urban centers and river valleys of Iraq and Iran (figure 1) [43,45].

In addition to sandfly fever, Desert Shield/Storm troops were evaluated for other acute arthropod-borne viral diseases, including dengue, Sindbis, West Nile fever, Rift Valley fever, and Crimean-Congo hemorrhagic fever [47,48]. Only one patient with West Nile fever, who presented with a 4-day self-limited course of high fever and arthralgias was identified [47].

No evidence of typhus or spotted fever-group rickettsia infection was found in the serologic evaluation of 37 febrile troops [47] and deployment serosurvey of 865 ground troops [48]. These data, plus the low occurrence of arboviral infections and leishmaniasis, indicate a very low risk overall of arthropod-borne diseases among U.S. troops during Operations Desert Shield and Desert Storm.

Other Infectious Diseases

Infectious diseases that historically have plagued military populations--malaria, sexually transmitted diseases (STDs), and viral hepatitis--were not a problem during this deployment of U.S. troops. Malaria has been eradicated in northeastern Saudi Arabia and Kuwait where most U.S. troops were stationed but still occurs in Iraq where coalition forces operated for only a brief period of time. Consequently, just seven cases of malaria due to Plasmodium vivax were reported among U.S. troops who had crossed into southern Iraq [12,38]. STDs also were an infrequent finding because of very limited contact between U.S. troops and other populations. As for acute hepatitis, only a few cases of hepatitis A and B were observed among U.S. troops because of prophylaxis with immune serum globulin, extensive prior screening of U.S. troops for the use of illicit drugs, and strict monitoring of the chlorination and purity of the potable water supply [49].

Brucellosis and Q fever are endemic in the Middle East and were a potential threat to the health of U.S. troops. To date, there has been no reported diagnosis of brucellosis among Desert Storm troops and only three cases of Coxiella burnetii infection [47,50]. The low risk of these two infectious diseases probably was due to the fact that only commercial, pasteurized cow milk products were provided to U.S. troops [51], local dairy production facilities were regularly inspected by U.S. military veterinary personnel [6], and most troops had very limited or no contact with herds of animals.

Other infectious diseases found in the Middle East were not a problem for Persian Gulf troops. There has been no reported case of schistosomiasis, echinococcosis, or active tuberculosis, but there were two cases of meningococcal disease [38].

Unexplained Illnesses

Since the end of the Gulf war, several thousand veterans from widely diverse military units have complained of chronic non-specific symptoms which have not been readily explained [5,42]. In the Department of Veterans Affairs and Department of Defense self-referred health registries of ill or concerned Persian Gulf veterans, the most common complaints have been chronic fatigue, headache, muscle and joint pain, shortness of breath, intermittent diarrhea, cough, and neuropsychological complaints, including sleep disturbance, difficulty concentrating, forgetfulness, irritability, and depression [42,52]. No documented fever, characteristic skin rash, or consistent abnormality in results of laboratory tests currently has been identified. There has been no published report of similar unexplained illnesses among >100,000 non-U.S. coalition troops [42], except that in June 1994 Great Britain's Ministry of Defense reported diverse, non-specific symptomatology in 33 veterans, which was consistent at that time with the normal incidence of these symptoms in that country's military population [53].

Various infectious diseases have been considered as possible causes of unexplained illnesses, including visceral leishmaniasis, brucellosis, Q fever, Lyme disease, tuberculosis, and retroviral infections [5,54]. However, these infectious diseases have not been found to be the cause of unexplained illnesses among 150 ill Gulf war veterans who were intensively evaluated at three Veterans Affairs referral centers [12,42]. In addition, evaluation of 27 symptomatic veterans found no increase in titers of serum antibody to two recently recognized infectious agents, Mycoplasma fermentans and M. penetrans (personal communication, Dr. Shyh-Ching Lo, Armed Forces Institute of Pathology, Washington, DC). Of note, arthropod-borne viral diseases endemic in the Persian Gulf, such as sandfly fever, are not known to cause chronic infection and disease [55].

Biologic warfare agents also have been suggested as a possible etiology of unexplained illnesses [56]. Iraq is suspected of having a program that produced Bacillus anthracis, Clostridium perfringens, and Clostridium botulinum [57], but there was no report during the war of casualties consistent with exposure to biological warfare agents [12]. In addition, these specific agents and their toxins are highly lethal in minute quantities and would not be expected to produce chronic, nonspecific symptoms years after exposure.

An unknown or emerging infectious disease has been hypothesized as a possible cause of unexplained illnesses [58], but evaluated veterans have had no unusual or characteristic symptoms or signs that would indicate a unique infectious process. Moreover, a National Institutes of Health Technology Workshop on the "Persian Gulf Experience and Health" held in April 1994 concluded that "no single or multiple etiology or biological explanation for the reported [unexplained] symptoms was identified from the data available to the panel," and that "no single disease or syndrome is apparent, but rather multiple illnesses with overlapping symptoms and causes" [5].

Some of the veterans with unexplained illnesses have presented with symptoms and signs consistent with a diagnosis of chronic fatigue syndrome [12]. On the basis of general population surveys that indicate that the crude prevalence of chronic fatigue syndrome may be >100 cases per 100,000 (personal communication, Dr. William C. Reeves, Viral Exanthems and Herpesvirus Branch, Centers for Disease Control and Prevention) [59], several hundred Desert Shield/Storm veterans could present with this medical condition. Preliminary evaluations of two groups of 85 and 37 symptomatic Gulf war veterans found a possible increase in titers of serum antibody to Epstein-Barr virus antigens [60,61], but these veterans have not been evaluated in controlled, blinded studies [62,63].

Because most veterans became ill several weeks to more than a year after returning to the United States, rather than after an illness while in the Persian Gulf [64], epidemic neuromyasthenia is an unlikely explanation for chronic fatigue and other generalized symptoms. In suspected outbreaks of epidemic neuromyasthenia, the incubation period appeared to be short and the onset of fatigue often coincided with an initial, flu-like, acute illness [65-67].

Conclusion

The incidence of nonbattle injuries, including infectious disease morbidity, was lower during Operations Desert Shield and Desert Storm than during any previous war involving U.S. military personnel [12,13]. The fact that infectious diseases were not a major cause of lost manpower, unlike the experience of Western troops in the Persian Gulf during World War II, can be attributed to a combination of factors. One important factor was the presence of a comprehensive infrastructure of medical care, which was capable of controlling any highly infectious disease like shigellosis [9,20]. Another major factor was the extensive preventive medicine effort by the U.S. military, which included continuous disease surveillance and rapid diagnostic support to quickly identify and correct health hazards [16]. In addition to these clinical and preventive medicine efforts, several fortuitous factors unique to this deployment contributed to a very low rate of infectious disease morbidity, principally isolation of troops in barren desert locations and cooler winter conditions during the height of the troop buildup.

Whether changes since World War II in the environment or the animal and human reservoir of infection in the Persian Gulf contributed to a low risk of infectious disease morbidity among U.S. troops also has to be considered. In Saudi Arabia and Kuwait, a modern health and sanitation system has been built and many previously endemic infectious diseases have been nearly eliminated in recent years, including schistosomiasis and malaria [68,69]. The decreased endemicity of infectious diseases in this region would have reduced the threat for coalition troops.

The primary cause of infectious disease morbidity among Desert Shield/Storm troops was generally mild acute diarrheal and respiratory disease, which was expected from prior experiences of deployed U.S. troops [18,19]. Because of the unavoidable crowding during a rapid mobilization for war and inevitable exposure to infectious disease pathogens, especially in tropical and developing countries, diarrheal and respiratory diseases will remain a problem for U.S. troops until effective vaccines are developed.

Although U.S. troops were at low risk of incapacitation from infectious diseases during the Persian Gulf war, other military campaigns may not be so fortunate. Chance events, like the time of year and geographic location of deployment, can have a major impact on the risk of transmission of infectious diseases and result in higher morbidity among deployed troops. History teaches that the outcome of future battles could be swayed by infectious diseases. Therefore, the U.S. military must continue to support an aggressive program of preventive medicine, which is guided during deployments by continuous disease surveillance and on-site laboratory analyses. In addition, it is critical for the military to maintain an infectious diseases research program to develop new vaccines, improved medical treatments, and more accurate and rapid diagnostic tests.

This work was supported by the U.S. Naval Medical Research and Development Command, NMC, NCR, Bethesda, Maryland.

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Table 1
Bacterial enteropathogens identified in stool samples from 432 U.S. military personnel with acute gastroenteritis during Operation Desert Shield (reprinted by permission of The New England Journal of Medicine, [16]).

* Thirty-six patients had mixed bacterial infections.
+ Two patients had individual colonies producing either heat labile toxin or heat stable toxin only.

For the following figures please click on the accompanying document:

Military Medicine in Operations Desert Shield and Desert Storm: The Navy Forward Laboratory, Biological Warfare Detection, and Preventive Medicine


Figure 1. Not included; please refer to Clin Infect Dis 1995;20:1497-1504, for map.

Figure 2. Weekly rates for total outpatient (sick call) visits among approximately 40,000 Marine Corps ground troops stationed in Northeaster Saudi Arabia who participated in the U.S. Navy disease surveillance system.

Figure 3. Weekly gastroenteritis outpatient rates among approximately 40,000 Marine Corps ground troops stationed in northeastern Saudi Arabia. The arrow indicates when fresh produce was removed from the diet following identification of enteric disease pathogens by preventive medicine personnel and the subsequent sharp decrease in the incidence of diarrheal disease.

Figure 4. Weekly respiratory disease outpatient rates among approximately 40,000 Marine Corps ground troops stationed in northeastern Saudi Arabia. The arrows indicate the two primary periods of time when U.S. Marine Expeditionary Force (MEF) personnel were being transported to the theater of operations, which also coincided with increased rates of respiratory disease.