Xerophthalmia and Keratomalacia

The WHO classification of xerophthalmia is shown in Table 3. This classification was first adopted in 1976 (126), with minor modification in 1982 (247). The ocular signs are

Fig. 5. Night blindness in a public health poster from Indonesia.

classified in order of severity from night blindness (XN) to corneal ulceration and kera-tomalacia that involves one-third of the cornea or greater (X3B). A corneal scar (XS) is not a sign of active vitamin A deficiency. Xerophthalmic fundus (XS) is usually considered to be a rare condition.

4.1.1. Night Blindness

Vitamin A is the biochemical precursor to rhodopsin, which is essential to the visual cycle in rod photoreceptors and night vision. The earliest clinical manifestation of vitamin A deficiency is often night blindness. Vision is normal during the day, but the vitamin A-deficient individual may have difficulty distinguishing objects at night. A typical history may involve a child who bumps into furniture or objects at night and is afraid to come to the mother when called. In areas where vitamin A deficiency is endemic, it is not uncommon that the condition is well recognized by local people and has a specific name, such as kwak moin "chicken blindness" in Cambodia, or buta ayam "chicken eyes" in Indonesia (chickens lack rod photoreceptors and have poor night vision). This phenomenon is shown in a public health poster from Indonesia (Fig. 5).

4.1.2. Conjunctival Xerosis

Vitamin A is essential for the maintenance of normal mucosal epithelia, including the conjunctiva. The normal conjunctiva consists of nonkeratinized columnar epithelium with mucin-secreting goblet cells. During vitamin A deficiency, there is loss of mucin and goblet cells, increased keratinization, and a transition to stratified squamous epithelium. The bulbar conjunctiva may appear dry and roughened, and on oblique illumination may have a pebble-like or bubbly appearance (Fig. 6). The surface of the epithelium may not easily be wetted by tears. Conjunctival xerosis is often associated with night blindness, an observation that was made as early as 1855 (25). Conjunctival xerosis is not considered a good diagnostic indicator of vitamin A deficiency, as it is often overdiagnosed in nutrition surveys. Bitot spots are a more well demarcated area of conjunctival xerosis and are considered separately under Subheading 4.1.3.

The pathological changes in the conjunctiva are related to the role that vitamin A plays in the regulation of mucin and keratin expression. In rats, membrane-spanning mucin ASGP (rMuc4) and secretory mucin rMuc5AC were downregulated during vitamin A deficiency (248). The alterations in mucin gene expression occurred in goblet cells and stratified epithelium of the cornea and conjunctiva, and once severe keratinization occurred, mRNA for rMuc5AC and ASGP were no longer detectable (248). In the rabbit model, vitamin A deficiency is associated with keratinization of the conjunctiva, with up-regulation of AE1 (56.5 kd), AE3 (65-67 kd), and AE2 (56.5 and 65-67 kd) keratins (249). Following treatment with vitamin A, the conjunctiva changes from keratinized, stratified squamous epithelium without goblet cells to normal columnar epithelium with goblet cells (250,251). The loss of keratinization following vitamin A therapy appears to precede the restoration of goblet cells, which appear more slowly in response to treatment (251).

Around the beginning of the nineteenth century, the terms "xerosis," "xerophthalmia," and "xerophthalmos" were often used to describe dryness and associated changes of the eye that were considered to be related to conditions such as exposure, scrofula, syphilis, trachoma, and dryness of the eyes in older adults (252-256). The term "xerophthalmia" was applied in relationship to night blindness, corneal ulceration, and keratomalacia after further clinical observations and the development of ideas in the 1860s (20,27).

4.1.3. Bitot Spot

A well demarcated patch of keratinized, squamous metaplasia of the bulbar conjunctiva, known as a Bitot spot, is considered pathognomonic for vitamin A deficiency. Pierre Bitot's original description from 1863 (20) is worth repeating:

"La forme de cette tache diffère non-seulement selon les sujets, mais encore aux deux yeux d'un même individu. En général, elle est triangulaire, à sommet externe; la base, voisine de la cornée, est un peu concave. Dans quelques cas, elle était circulaire ou ovalaire; dans d'autres, simplement linéaire. Le plus souvent, les particules qui la composent sont agglomérées de façon à constituer une surface ponctuée, chagrinée; d'autres fois ces particules se disponsent en séries ou lignes flexueuse, parallèles, qui donnent à la tache l'aspect d'une surface ondulée ou ridée."

Xerosis Oeil
Fig. 6. Conjunctival xerosis. (Courtesy of Task Force Sight and Life.)

"The shape of this patch differs not only from subject to subject, but also differs from eye to eye in the same individual. In general, it is triangular [a sommet externe], the base, which is near the cornea, is slighty concave. In some cases, it was circular or oval; in others, simply linear. Mostfrequently, the particles that compose it are grouped in such a way as to make up a stippled, distressed surface; in other cases these particles are arranged in a series or in flexible parallel lines that give the patch the appearance of a wavy or wrinkled surface."

Bitot spots are usually located on the temporal bulbar conjunctiva in the interpalpebral zone of one or both eyes. The spots may have a foamy, "cheesy," "greasy," or granular appearance (Fig. 7). If vitamin A deficiency is more severe or longstanding, Bitot spots may also be found on the nasal bulbar conjunctiva on one or both eyes. Thus, any combination of one to four Bitot spots may be found in one individual. The number of Bitot spots generally correlates with the severity of vitamin A deficiency and low serum retinol concentrations (257). It appears that if the Bitot spots are longstanding, there may be a point beyond which the keratinizing squamous metaplasia is irreversible even with vitamin A supplementation. Bitot spots that do not respond to vitamin A therapy have been termed "nonresponsive Bitot spots," and this phenomenon gave rise to earlier observations of Bitot spots in individuals with normal serum retinol concentrations (258,259). If the spots are rubbed or scraped off the bulbar conjunctiva, they usually reappear after a few days if the patient has not received substantial improvement in vitamin A intake through diet or supplementation.

The histopathology of Bitot spots has been studied extensively and described repeatedly in the scientific literature (20,260-276). The lesion consists of keratinized squa-mous epithelium with keratohyalin granules in the granular layer. The surface of the lesion may contain desquamated epithelial cells, amorphous debris, and bacteria and/or fungi. Goblet cells are absent. No differences in histopathology have been noted between

Tache Bitot
Fig. 7. Bitot spot. (Courtesy of Task Force Sight and Life.)

Bitot spots that are responsive or nonresponsive to vitamin A treatment; however, in the latter, the conjunctiva surrounding the Bitot spot is relatively normal (275). Many investigators have described the presence of a Gram-positive bacillus, Corynebacterium xerosis, in Bitot spots. The organism, also known as Bacillus xerosis, Bacterium xerosis and Bacterium colomatti, and Corynebacterium conjunctivae, received its present designation from Karl Lehmann (1858-1940) and Rudolf Neumann (1868-1952) in 1899 (277). The bacteria appears to be a commensal organism that does not normally produce eye pathology. P. Colomiatti described an organism from Bitot spots taken from young boys in a correctional institution (278). John Elmer Weeks (1853-1949) obtained pure cultures of the "double bacillus" and inoculated a rabbit cornea using a Graefe knife that had been dipped in the bacterial culture. The cornea healed without suppuration. Other experiments were conducted in with inoculations in the conjunctival sac, and the rabbit developed no reaction (261). Studies conducted by Eugen Fraenkel (1853-1925) and Ernst Franke (1857-1925) at the Allgemeinen Krankenhause in Hamburg, showed that xerosis bacillis were nonpathogenic (279). In 1898, Stephenson attempted to induce xerosis in another human subject by inoculation of the conjunctiva with the frothy material from the conjunctiva and by injecting the conjunctiva of another subject with pure cultures of the xerosis bacilli; this inoculation produced no resulting pathology (280).

4.1.3. Corneal Xerosis

With more severe vitamin A deficiency, the cornea may also undergo squamous metaplasia with keratinization, and the cornea appears hazy and rough instead of smooth and transparent (Fig. 8). The earliest change in corneal xerosis is a punctate keratitis characterized by fine pin-point lesions in the corneal epithelium (281-284). The punctate keratitis is more visible with fluorescein staining, and the intensity of the punctate keratitis is

Taches Bitot
Fig. 8. Corneal xerosis. (Courtesy of Task Force Sight and Life.)
Xerosis Rnea
Fig. 9. Corneal xerosis with desquamated epithelium. (Courtesy of Task Force Sight and Life.)

greatest in the inferonasal part of the cornea (283). Corneal xerosis may be more apparent in the inferior portion of the cornea, and there may be underlying stromal edema that is detectable on slit lamp examination (285). In more severe disease, the cornea has a peau d'orange appearance, and there may be accumulations desquamated, cornified epithelium that may slough off or form large xerotic plaques on the cornea (285) (Fig. 9). Foreign body sensation, photophobia, and irritation have been described in patients with corneal xerosis (285).

Corneal Keratinization
Fig. 10. Corneal ulcer. (Courtesy of Task Force Sight and Life.)

In the vitamin A-deficient rat, keratinization occurs in the corneal epithelium with thickening of the stroma (286). The changes occur without any evidence of a preinflam-matory lesion or bacterial infection (286). Pathological changes in the cornea of vitamin A-deficient mice included keratinizing epithelium with loosened outer layers and kera-tohyalin granules in cells of the intermediate and superficial regions, variegated, invagi-nated nuclei and mitochondria of the basal cells, and occasional free and phagocytized bacteria on the loosened outer layers of the keratinized epithelium (287). In vitamin A-deficient guinea pigs, punctate corneal irregularities were common, and scanning electron microscopy showed extensive areas of surface epithelial cells lifting off the cornea and large, mound-like irregular projections distributed sparsely over the plasmalemma, in comparison to primary microvilli and no evidence of plasmalemmal disruption in vitamin A-sufficient control animals (273). Studies in vitamin A-deficient rabbits showed multiple punctate epithelial erosions that progressed with a peau d'orange appearance and later with development of polycystic microbullae in the central region of the cornea with underlying stromal edema (288). In more severe deficiency, necrotizing stromal infiltrates developed beneath keratinized plaques, with eventually ulceration of the corneal stroma (288). Vitamin A deficiency also affects glycoprotein synthesis in the rat corneal epithelium (289).

4.1.5. Corneal Ulcer

Corneal ulceration may follow corneal xerosis, and the typical corneal ulcer associated with vitamin A deficiency is round or oval with a relatively clean, punched-out appearance, as if the cornea had been altered with a small trephine (Fig. 10). With full-thickness ulceration, the iris may prolapse through the ulcer. Secondary infection may occur. In a large series of 100 patients with vitamin A deficiency and xerophthalmia in the Philippines, among those with corneal ulceration or perforation, the most common isolates were Pseudomonas aeruginosa, Streptococcus pneumoniae, and Moraxella spp., with P. aeruginosa cultured from 35% of cases that had a corneal perforation (290). Most of the subjects had concurrent infections such as gastroenteritis, bronchopneumonia, and upper respiratory infection, and about one-third had severe malnutrition.

Experimental animal studies show that the healing process is impaired after various traumatic injuries to the cornea in vitamin A deficiency. After epithelial abrasions of the cornea, vitamin A-deficient rats progressed to extensive epithelial defects and stromal ulceration, often with an intense inflammatory reaction and bacterial infection (291). Impaired wound healing was also observed in vitamin A-deficient rabbits (292). Recovery from thermal burns to the cornea was slower in vitamin A-deficient compared with control rats (293), and polymorphonuclear leukocytes appear to play a role in the worsening of ulcerative lesions (294). Vitamin A deficiency appears to be associated with impaired epithelial migration and impaired production of fibronectin, a glycoprotein that plays a role in adhesion, chemotaxis, and tissue repair (295). The plasminogen activator-plasmin system has been implicated in corneal ulceration (296), but lack of tissue plas-minogen activator has been found in the center of induced corneal wounds in vitamin A-deficient rats (297). After mechanical abrasion of the cornea in vitamin A-deficient rats, infiltrates of polymorphonuclear leukocytes were observed, but reepithelialization occurred without severe stromal degradation (298). In contrast, stromal incision in vitamin A-deficient rats resulted in marked stromal degradation, which suggested that stromal injury was more important than polymorphonuclear leukocytes in the pathogenesis of corneal ulceration in vitamin A deficiency (298). Vitamin A-deficient rabbits in the late stages of xerophthalmia were more susceptible to experimental infection with P. aeruginosa than animals in the early stages of xerophthalmia or control animals (299). Following induced trauma, P. aeruginosa infection and ulceration were worse in vitamin A-deficient compared with control rats (300). The production of collagen in rabbit corneal keratocytes is modulated by retinoids, which suggests an additional mechanism for vitamin A in the maintenance of cornea integrity (301).

Matrix metalloproteinases, collectively known as matrixins, are proteinases that are involved in degradation of the extracellular matrix, and these include collagenases, gela-tinases, stromelysins, and matrilysins (302). Corneal ulceration in vitamin A deficiency is influenced by the production of proteinases, which can be produced by the cornea (303308), inflammatory cells (309), and bacteria (310). The expression of different protein-ases in the cornea may vary during vitamin A deficiency and might explain conditions that occur with differences in proteolysis. Under conditions of vitamin A deficiency, with decreased proteolysis, epithelial cells may not exfoliate properly, and with increased proteolysis, superficial punctate keratopathy and increased corneal keratocyte loss may occur (311). Cathepsin D, an aspartic proteinase, was increased threefold in the corneas of vitamin A-deficient rabbits compared with pair-fed control rabbits (311). The production of collagenase in the cornea is increased in vitamin A-deficient rats compared with control rats (293,305).

Retinoids modulate the expression of numerous proteins such as matrix metallopro-teinases and plasminogen activator through alteration of gene transcription and through interaction of retinoic acid receptors with transcription factors such as c-Jun and c-Fos at the activator protein (AP)-1 site (312). The promoter region of the collagenase gene contains an AP-1 responsive element that is repressed by retinoic acid (313). RARs do not appear to bind directly to the AP-1 site but appear to bind with c-Jun to form an inactive

What Does Plasminogen
Fig. 11. Keratomalacia. (Courtesy of Task Force Sight and Life.)

complex that does not upregulate collagenase expression (313-315). Interleukin (IL)-1, a potent mediator of inflammation, shows increased activity in the cornea of vitamin A-deficient rats after mechanical injury in comparison to corneas of control rats (316). IL-1 stimulates and retinoic acid inhibits collagenase transcription through inhibition of c-Fos (317). The combination of increased IL-1 activity and deficiency in retinoic acid may both potentially contribute to the increased expression of collagenase in corneal ulceration and keratomalacia associated with vitamin A deficiency.

4.1.6. Keratomalacia

Keratomalacia is characterized by melting of the cornea (Fig. 11). In the late 19th century, keratomalacia was not uncommon in Europe and was noted primarily among young infants. Albrecht von Graefe (1828-1870) noted: "although the illness concerned here is not exactly a frequent one, hardly a semester passes when I do not see an incidence of it, and at times I have seen three or four cases within a month. The general picture offered, with some variation of details, is uniform to such an extent that I always held to the idea that a constant general affection must be present in the organism" (318). Von Graefe found that the illness usually occurred within a few weeks of birth, especially among infants with pale appearance, loss of tone, poor nutrition, decline in appetite, and diarrhea (318). Von Graefe recognized that the condition began with a lesion of the bulbar conjunctiva that was "dull, dry, covered with fine scales and raised in appearance with perpendicular wrinkles" and "depleted of its natural moisture," and that this "acute xerosis" was connected to the corneal destruction that followed. Von Graefe attributed the corneal ulceration to encephalitis, since autopsy findings had suggested brain inflammation among infants who had died with keratomalacia. Julius Hirschberg (1843-1925), a disciple of Von Graefe, described how apparently healthy infants developed anorexia, diarrhea, marasmus, and then rapidly progressed with xerophthalmia in both eyes (319). Intestinal helminthiasis increases the risk of keratomalacia in children (320,321). Keratomalacia was described in a child with familial hypo-retinol-binding proteinemia (322) and also has been described in acrodermatitis enteropathica (323).

Keratomalacia has also been described among adults, usually in association with severe diarrheal disease (324-326), and sometimes in association with unusual dietary practices, alcoholism, and severe cachexia (see Subheading 5.3.10.). The ocular pathology of keratomalacia has been described in a few reports (327,328), including a 27-yr-old woman who followed a "cult" vegetable and grain diet, developed night blindness, keratomalacia, and died (328). Bilateral corneal melting was noted with minimal inflammatory reaction, despite a large corneal perforation. Keratomalacia has been produced in vitamin A-deficient animals (329). A discussion of the biological mechanisms that have been implicated in the pathogenesis of corneal ulceration and keratomalacia was discussed under Subheading 4.1.5. Secondary infection may play a role in keratomalacia (330) but does not appear to be the initiating event (331). Some investigators believe that protein malnutrition is an important contributing factor to keratomalacia because of keratomalacia is more common among individuals with protein energy malnutrition (332,333).

4.1.7. Xerophthalmic Fundus

Xerophthalmic fundus (fundus xerophthalmicus) is a condition characterized by fine white, cream-colored, or greyish dot-like, oval, or linear opacities in the retina. It usually occurs among individuals with night blindness, conjunctival xerosis and/or Bitot spots. In 1894 in Freiburg, Karl Baas (1866-1944) described a 15-yr-old field hand with night blindness, conjunctival xerosis, and a large amount of small white dots located in the retina (334). The condition was associated with liver disease and called "ophthalmia hepatitica." Otmar Purtscher (1852-1927) described more cases of "ophthalmia hepati-tica" in Klagenfurt, Austria in 1900 (335). In 1915, Sanroku (or Saroku) Mikamo described a 12-yr-old boy from Fukuoka, Japan who had night blindness (336). The boy worked for a rice dealer and was known to have been healthy all his life. He began to bump into furniture at night and had dropped a rice bowl, and even after scolding, he continued to have difficulty making his way around when it became dark. One evening he was pouring water into a tub to take a bath, and his friends were astonished to see him pouring the water onto the ground, as he could not see well and had missed the tub completely. The following day he was taken to the eye hospital, where it was noted that he had Bitot spots and small white dots in the equatorial zone of the fundus of both eyes. The fundus findings were depicted (Fig. 12) (336). The patient was noted to have a narrowed visual field, and laboratory investigations revealed that the boy had hookworm infection. During treatment with cod-liver oil, the night blindness and Bitot spots disappeared after a few days, but it took several weeks for all the white dots in the fundus to disappear (336).

In 1922, Robert E. Wright described "a mid-peripheral belt of discreet white spots" in the fundus of patients with night blindness and keratomalacia in Madras, India (337). Misao Uyemura reported two cases of xerophthalmic fundus in 1928 seen at the eye clinic of Keio University in Tokyo (338), and the condition became known later as Uyemura's syndrome (339). Adalbert Fuchs (1887-1973) described another case while he was a

Xerophthalmic Fundus
Fig. 12. Fundus xerophthalmicus. (From ref. 336.)

visiting professor at Peking Union Medical College (340), and additional cases were described in Japan (339,341,342), China (343,344), Italy (345,346), and Germany (347). The retinal lesions are located most commonly in the peripheral retina and are usually found in both eyes. As noted by Teng Khoen Hing: "It is striking that in the flourishing cases, where it looks as if they have been scattered lavishly over the surface of the fundus, the granules are glaringly white like sugared caraway seeds. In these cases, we see many 'sugared caraway seeds' grow together to ramify like a clover-leaf, or we see them in a row along the vessels, so that the vessels look as if they get a shell in their course in some places" (348). The whitish lesions are located deeper in the retina than the retinal blood vessels. In 1933, Yatsutake described bilateral visual field constriction in a patient with xerophthalmic fundus (342).

Although xerophthalmic fundus is often described as a rare condition, most individuals who are encountered in the field with Bitot spots and/or night blindness do not generally receive a dilated fundus examination and the condition may be overlooked. In the largest published cases series, Teng Khoen Hing examined hundreds of outpatients seen at the Cicendo Eye Hospital in Bandung, Indonesia who had xerophthalmia in a period from about 1956 to 1961 (349). Of 190 subjects with night blindness, 23.7% had xerophthalmic fundus, and of 600 subjects with conjunctival xerosis, Bitot spots, corneal xerosis, or keratomalacia, 35% had xerophthalmic fundus. The highest prevalence of xerophthalmic fundus was found among children aged 5-14 yr. Of 321 cases of xerophthalmic fundus that were reported, 93% had night blindness, conjunctival xerosis, or both (349, 350). An additional case of xerophthalmic fundus was described from Cicendo Eye Hospital in 1978 (351). The severity of xerophthalmic fundus appears to correlate with more longstanding vitamin A deficiency and lower serum vitamin A concentrations (352,353). The highest risk group for xerophthalmic fundus appears to be those in the age group from 5 to 14 yr (350). Xerophthalmic fundus can usually be differentiated from other fundus conditions with white dots, such as retinitis punctata albescens and fundus albipunctatus,

Vitamin Deficiency Fundus
Fig. 13. Rat model, changes in outer segments after vitamin A-deficient diet for 23 wk. (Reprinted from ref. 360, with permission of Investigative Ophthalmology and Visual Science.)

because xerophthalmic fundus is often associated with other signs of vitamin A deficiency (conjunctival xerosis, Bitot spots, corneal xerosis, and so on), and the white lesions resolve after treatment with vitamin A (350).

Vitamin A deficiency has been shown to induce histopathological changes in the rod photoreceptors of the retina in experimental animal models (354-360). These changes consist of degeneration of rod outer segments, the external limiting membrane, the retinal pigment epithelium, the outer molecular layer and the inner nuclear layer (356,357). The pathological changes in rod outer segments with prolonged vitamin A deficiency in the rat model includes distention or dispersion of disc into vesicles, and the appearance of vesicles in the pigment epithelium and between processes of the pigment epithelium (Fig. 13). In contrast, normal rod outer segments show regular organization of outer

Leucoma Corneal
Fig. 14. Corneal scar. (Courtesy of Task Force Sight and Life.)

segment discs and close contact with processes of the pigment epithelium (360). Autoradiographic studies show that the rate of rod outer segment renewal and removal is impaired by vitamin A deficiency (361). Vitamin A-deficient rats with degeneration of the rod photoreceptors may recover to almost normal appearance after refeeding with vitamin A over 10 to 18 wk (357). Refeeding of deficient animals is associated with an increase in rod outer-segment density (362).

Xerophthalmic fundus has been described in a 20-yr-old man who stopped consuming food sources of vitamin A for about 5.5 yr because he thought it would reduce his epileptic seizures (363,364). His serum retinol concentrations were as low as 0.14 pmol/L when he was seen as an outpatient (363). The patient refused any treatment with vitamin A and later developed bilateral corneal xerosis. He was eventually admitted on an emergency basis to the hospital with fever, anorexia, abdominal pain, and corneal ulceration. After treatment with daily vitamin A therapy for 3 mo, the yellowish dots in the fundus decreased in size and disappeared (365). A hereditary defect in the gene for serum RBP, a heterozygous missense mutation Ile41Asn and Gly75Asp, is associated with xerophthalmic fundus (366). Fundus examination of two siblings with the condition showed small dots representing focal loss of retinal pigment epithelium (366). The white dots characteristic of xerophthalmic fundus appear as window defects in the retinal pigment epithelium in fluorescein angiograms (351).

4.1.8. Corneal Scar

The sequelae to corneal ulcer and keratomalacia include the formation of a corneal scar or leucoma (Fig. 14). Corneal scarring can arise from causes other than vitamin A deficiency, such as following trauma and infectious keratitis unrelated to vitamin A, thus, the interpretation of corneal scarring must be made with caution in surveys. The corneal scarring that occurs with measles and vitamin A deficiency cannot be distinguished from corneal scarring from vitamin A deficiency without measles. Many surveys of the causes


Handbook of Nutrition and Ophthalmology

Table 4

Vitamin A and Immune Function


Effect of vitamin A deficiency

Maintenance of mucosal surfaces

Loss of cilia in respiratory tract

Loss of microvilli in gastrointestinal tract

Loss of goblet cells and mucin in respiratory,

gastrointestinal, and genitourinary tracts

Squamous metaplasia of conjunctiva, cornea with loss

of goblet cells and mucus and keratinization of ocular


Function of immune effector cells

Impaired neutrophil, natural killer cell, monocyte/

macrophage, and lymphocyte function

Altered cytokine production

Impaired T- and B-cell activation

Antibody production

Impaired antibody responses to T-cell-dependent antigens

and T-cell-independent type 2 antigens


Altered T-cell subsets

of blindness in schools for the blind may simply classify the corneal scarring as due to "vitamin A deficiency/measles." The prevalence of vitamin A deficiency as ascertained by institutional surveys should be considered extremely conservative estimates, since corneal ulceration and keratomalacia are associated with high mortality rates. In Hyderabad, India, a longitudinal study of 32 children who had been hospitalized for keratomalacia revealed that nearly one-third died within 3 to 4 mo after discharge from the hospital (367).

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