Cytomegalovirus enteritis in common variable immunodeficiency.

Abstract: A woman with previously undiagnosed common variable immunodeficiency presented with diarrhea and volume depletion. Biopsies from upper and lower endoscopy revealed atrophic gastritis, villous atrophy, and an inflammatory bowel disease-like chronic colitis, with absence of plasma cells in all sites. Cytomegalovirus inclusions were demonstrated in the colon and small bowel mucosa. Despite therapy with intravenous immunoglobulin and ganciclovir, the patient deteriorated rapidly and subsequently died. This case report highlights the potential for cytomegalovirus to cause extensive disease in patients with common variable immunodeficiency and, thus, the importance of considering it in the initial differential diagnosis so that further morbidity and mortality might be prevented.

Key Words: common variable immunodeficiency, cytomegalovirus, diarrhea

**********

Common variable immunodeficiency (CVID) is primarily a disorder of B-cell differentiation; in some cases T-lymphocyte dysfunction may be seen as well. (1), (2) Patients display decreased antibody synthesis and a propensity for recurrent sinopulmonary disease. (1), (2) Cytomegalovirus (CMV) infection is an infrequent complication of this disorder, and very few cases of resulting gastrointestinal disease have been reported. We describe a case of CMV enteritis in a patient with CVID that led to severe illness and, ultimately, death.

Discussion

CVID is a clinically and immunologically heterogeneous disorder characterized by hypogammaglobulinemia, recurrent bacterial infection, and an increased incidence of malignant and autoimmune disease. The underlying pathogenesis is due to a failure of terminal B-lymphocyte differentiation, resulting in immature B-cells that are unable to transform into antibody-secreting plasma cells. (1), (2) Thus the hallmark of this disorder is a decrease in serum immunoglobulin levels, with IgG and IgA being more severely affected than IgM. In most patients, the absolute number of B-lymphocytes remains normal or only slightly decreased, and the initial proliferative response to antigen exposure remains intact. (2) In addition to these B-cell abnormalities, abnormalities in T-cell activation have also been found in some patients. For example, cell-mixing studies have shown that some patients have T-cells that are capable of suppressing immunoglobulin production by normal B-cells. (2-4) Decreased T-cell proliferation and diminished production of cytokines including IL-2, IL-4, IL-5, and interferon [gamma] (IFN-[gamma]) have been noted, suggesting that a signaling defect may be present in a subset of patients. (5) The ratio of C[D.sup.4+] to C[D.sup.8+] T-cells may be reduced and is usually associated with an increase in T-suppressor activity along with a deficiency of helper T-cells, although the functional significance of this finding remains unclear. (5), (6)

The diagnosis of CVID is made by detecting a decrease in at least two immunoglobulin isotypes (IgG, IgA, or IgM) by two or more standard deviations below the mean. (1), (5) As evidenced by this case report, immunoglobulin levels may be greatly reduced or nearly undetectable in severe cases. In addition, patients demonstrate poor or absent response to immunization, manifest by a twofold or less increase in antibody titer. When immunoglobulin levels are severely depressed, confirmatory tests may not be needed. (7) However, if they are only slightly decreased in a patient with recurrent infection, a confirmatory test is necessary. This may include absence of appropriate response to tetanus, diphtheria, influenza, or pneumococcal vaccination. CVID is partially a diagnosis of exclusion, in that other primary antibody deficiencies such as X-linked agammaglobulinemia and hyperimmunoglobulin M syndrome must not be present. The disorder can occur at any age, but usually presents in the second or third decade. However, it may be diagnosed much later in life or may be missed altogether. As demonstrated in this case report, several years may pass between the onset of symptoms and the time of diagnosis. No molecular genetic defects have yet been definitively identified in this disorder, and most cases are sporadic. There has been some suggestion, of a genetic relationship between CVID and IgA deficiency. (2), (5)

[FIGURE 1 OMITTED]

Clinically, CVID is manifest by recurrent bacterial infections, particularly involving the upper and lower respiratory tract. Typically encapsulated bacteria including Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus are involved, resulting in sinusitis, otitis media, bronchitis, and pneumonia. (2) When untreated, chronic sinusitis or bronchiectasis may result. A variety of autoimmune and lymphoproliferative disorders are also seen. These include autoimmune hemolytic anemia and thrombocytopenia, rheumatoid arthritis, sicca syndrome, autoimmune thyroid disease, Addison's disease, diabetes mellitus, systemic lupus erythematosis, primary biliary cirrhosis, polymyositis, and alopecia totalis. (2), (7) The incidence of malignant lymphoma is increased as is benign lymphoproliferation manifested by splenomegaly or diffuse lymphadenopathy. (1), (2) A relationship between CVID and sarcoidosis has also been suggested. (8), (9) Affected patients have hilar lymphadenopathy and a reticular pattern is shown on chest x-ray, with noncaseating granulomas in the lungs, liver, spleen, and skin. In addition there appears to be an association with arthritis, consisting of either a nondestructive oligoarticular arthritis affecting the knees and ankles or septic arthritis with encapsulated bacteria. (2)

[FIGURE 2 OMITTED]

Gastrointestinal involvement in CVID has been well documented. (7), (10), (11) The majority of untreated patients develop diarrhea that can be quite severe, resulting in malnutrition and weight loss. Of the infectious causes, Giardia lamblia is the most common and may result in chronic infection. (5) Enteric infections with Salmonella, Shigella, Yersinia, Campylobacter, and Cryptosporidium also occur. A malabsorption syndrome characterized by steatorrhea, protein-losing enteropathy, disaccharidase deficiency, and vitamin deficiency may be seen. In addition, a granulomatous enteropathy can occur that appears to be distinct from inflammatory bowel disease, with granulomas distributed throughout the gastro-intestinal tract. (11) In some patients, including the one described above, features suggestive of inflammatory bowel disease or celiac sprue have been documented. (12) Gastrointestinal lesions may resemble either ulcerative colitis or Crohn's disease, but certain features of these diseases are lacking. For example, plasma cells are absent or greatly decreased, in contrast to inflammatory bowel disease, where plasma cells are numerous. It was notable that, in the patient described above, plasma cells were conspicuously absent in all specimens obtained. In addition, patients with malabsorption have been shown to have significant villous atrophy and chronic inflammatory infiltrate on small bowel specimens. However, in contrast to celiac sprue, enterocyte maturation appears normal, with preservation of the brush border. Again plasma cells are notably absent, and these patients generally do not respond or respond only transiently to withdrawal of gluten from the diet. (12) Finally, the incidence of neoplasm is increased and nearly a third of CVID patients with gastrointestinal manifestations eventually develop adenocarcinoma or lymphoma of the stomach, small intestine, or colon. (10) Non-Hodgkin's lymphoma is the most common malignancy and occurs in approximately 8% of affected individuals, with the small intestine being the most frequently affected gastrointestinal site. (1)

Other gastrointestinal findings can include an increase in lymphocytes in the lamina propria of the stomach as well as increased apoptosis in gastric epithelial cells. In CVID patients presenting with dyspepsia, the incidence of Helicobacter pylori infection was 41% in one study. (13) All of these patients, as well as 20% of H. pylori-negative patients, had chronic gastritis, and many also had multifocal atrophic gastritis. Pernicious anemia develops in approximately 10% of CVID patients and is characterized by an earlier age of onset and an absence of antiparietal cell antibodies. (2) Nodular lymphoid hyperplasia (NLH) is a common finding as well, occurring in 20 to 60% of patients, and results from the formation of large lymphoid follicles in the lamina propria and submucosa. These follicles cause protrusion of the overlying mucosa and result in a nodular or polypoid appearance. (10) Lesions may be widespread, with distal small bowel nodules tending to predominate. They can be found in the large intestine as well, where they are typically larger in size. Although nodular lymphoid hyperplasia is not considered a malignant disorder, malignant lymphomas often do arise in the setting of NLH.

Patients with CVID generally respond normally to viral infections, with some exceptions. Chronic enteroviral infection, particularly meningoencephalitis, has been reported and may lead to progressive neurologic deterioration. (14) Severe infections with varicella, herpes simplex virus, and measles have been reported. (2), (15), (16) Few cases of CMV disease in CVID patients have been recorded in the literature. These include isolated cases of CMV lymphadenitis, pneumonia, and gastrointestinal involvement. (17), (18) We found five cases of CMV enteritis in CVID patients recorded in the literature, the first in 1977. (1), (19-22) Of these, two were treated with ganciclovir with partial response. (20), (22) One occurred before the introduction of ganciclovir and resulted in fatality, and the remaining two reports did not contain specific information regarding treatment or outcome. In immunologically intact individuals, CMV results in either asymptomatic infection or a mononucleosis syndrome consisting of fever, myalgia, sore throat, rash, lymphadenopathy, and hepatosplenomegaly. However, in immunocompromised individuals, infection can lead to mucosal ulceration of the gastrointestinal tract with subsequent pain, diarrhea, bleeding, and perforation. (22) The risk of CMV disease is increased in patients who are recipients of solid organ or bone marrow transplants, individuals with malignancies and rheumatological disease, patients with acquired immunodeficiency syndrome (AIDS), and individuals receiving immunosuppressive therapy. (20) However, it seems that the incidence of CMV infection is not increased in CVID patients. (23)

A viral origin for CVID has been postulated in a subset of patients. (24) This is based on the fact that most C[D.sup.8+] T-cells from patients displaying inverted C[D.sup.4+]/C[D.sup.8+] ratios coexpress the CD57 and HLA-DR molecules, a phenotype also seen in patients infected with viruses including CMV, Epstein-Barr virus, and human immunodeficiency virus. (22) In addition, CMV mononucleosis and pneumonia have been shown to precipitate hypogammaglobulinemia. (25), (26) Based on these findings, it has been suggested that chronic viral infection might play a causative role in CVID. However, in the majority of patients there is no clinical evidence of viral disease. Although an initial report suggested an increase in CMV antigenemia in these individuals, a subsequent larger study found that the incidence of CMV infection is not significantly increased when compared with controls. (23), (27) However, when present in patients with CVID, disease resulting from CMV infection can be severe, as demonstrated in this case report.

In the patient described above, the diagnosis of CVID was made by endoscopic and pathologic findings and confirmed by detection of severely diminished serum immunoglobulin levels in the setting of chronic recurrent sinopulmonary disease. This diagnosis was made many years after symptom onset and only after the patient had become significantly debilitated. Had her condition been suspected earlier in the course of disease, later complications might have been avoided. CVID should be considered in all patients that present with recurrent bacterial infection. In addition, due to its potential to cause severe disease, CMV should be included in the differential diagnosis of CVID patients with gastrointestinal symptoms so that further morbidity and mortality might be prevented.

From the Departments of Medicine and Pathology, Vanderbilt University Medical Center, Nashville, TN.

Reprint requests to Glenn M. Eisen, MD, MPH, Associate Professor of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, 1501 TVC, Nashville, TN 37232-5280. Email: [e-mail]

Accepted November 9, 2002.

Copyright [c] 2004 by The Southern Medical Association 0038-4348/04/9701-0096

References

(1.) Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: Clinical and immunological features of 248 patients. Clin Immunol 1999;92:34-48.

(2.) Sneller MC. Common variable immunodeficiency. Am J Med Sci 2001;321:42-48.

(3.) Ashman RF, Saxon A, Stevens RH. Profile of multiple lymphocyte functional defects in acquired hypogammaglobulinemia, derived from in vitro cell recombination analysis. J Allergy Clin Immunol 1980;65:242-256.

(4.) de la Concha EG, Oldham G, Webster AD, et al. Quantitative measurements of T- and B-cell function in "variable" primary hypogammaglobulinaemia: Evidence for a consistent B-cell defect. Clin Exp Immunol 1977;27:208-215.

(5.) WHO Scientific Group. Primary immunodeficiency disease: Report of a sponsored meeting. Clin Exp Immunol 1995;99:1-24.

(6.) Wright JJ, Wagner DK, Blaese RM, et al. Characterization of common variable immunodeficiency: Identification of a subset of patients with distinctive immunophenotypic and clinical features. Blood 1990;76:2046-2051.

(7.) Chapel HM. Fortnightly review: Consensus on diagnosis and management of primary antibody deficiencies. BMJ 1994;308:581-585.

(8.) Fasano MB, Sullivan KE, Sarpong SB, et al. Sarcoidosis and common variable immunodeficiency. Report of 8 cases and review of the literature. Medicine (Baltimore) 1996;75:251-261.

(9.) Mechanic L, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med 1997;127:613-617.

(10.) Ament ME. Immunodeficiency syndromes and the gut. Scand J Gastroenterol Suppl 1985;114:127-135.

(11.) Mike N, Hansel TT, Newman J, et al. Granulomatous enteropathy in common variable immunodeficiency: A cause of chronic diarrhea. Postgrad Med J 1991;67:446-449.

(12.) Washington K, Stenzel TT, Buckley RH, et al. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol 1996;20:1240-1252.

(13.) Zullo A, Romiti A, Rinaldi V, et al. Gastric pathology in patients with common variable immunodeficiency. Gut 1999;45:77-81.

(14.) McKinney R, Katz S, Wilfert C. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis 1987;9:334-356.

(15.) Straus S, Seidlin M, Takiff H, et al. Oral acyclovir to suppress recurring herpes simplex virus infections in immunodeficient patients. Ann Intern Med 1984;100:522-524.

(16.) Hausser C, Virelizier JL, Buriot D, et al. Common variable hypogammaglobulinemia in children. Clinical and immunologic observations in 30 patients. Am J Dis Child 1983;137:833-837.

(17.) Sewell WA, Marshall SE, Mullighan CG, et al. A hypogammaglobulinaemic man with respiratory failure. Postgrad Med J 1998;74:503-504.

(18.) Scully RE, Mark EJ, McNeely WF, et al. Case reports of the Massachusetts General Hospital: Weekly clinicopathological exercises-Case 7-1995: A 58-year-old man with common variable immunodeficiency, splenomegaly, and hemolytic anemia. N Engl J Med 1995;332:663-671.

(19.) Freeman HJ, Shnitka TK, Piercey JR, et al. Cytomegalovirus infection of the gastrointestinal tract in a patient with late onset immunodeficiency syndrome. Gastroenterology 1977;73:1397-1403.

(20.) Buckner FS, Pomeroy C. Cytomegalovirus disease of the gastrointestinal tract in patients without AIDS. Clin Infect Dis 1993;17:644-656.

(21.) Yousry TA, Strupp M, Bruning R. Common variable immunodeficiency leading to spinal subacute combined degeneration monitored by MRI. J Neurol Neurosurg Psychiatry 1998;64:663-666.

(22.) Tahan V, Dobrucali A, Canbakan B, et al. Cytomegalovirus infection of gastrointestinal tract with multiple ulcers and strictures, causing obstruction in a patient with common variable immunodeficiency syndrome. Dig Dis Sci 2000;45:1781-1785.

(23.) Mullighan CG, Read SJ, Bird AG, et al. Human cytomegalovirus infection is not increased in common variable immunodeficiency. J Clin Immunol 1996;16:272-276.

(24.) Spickett GP, Millrain M, Beattie R, et al. Role of retroviruses in acquired hypogammaglobulinaemia. Clin Exp Immunol 1988;74:177-181.

(25.) Pahwa S, Kirkpatrick D, Ching C, et al. Persistent cytomegalovirus infection: Association with profound immunodeficiency and treatment with interferon. Clin Immunol 1983;28:77-89.

(26.) Greenberger PA, Walker CL, Fitzsimons TE, et al. Hypogammaglobulinemia associated with cytomegalovirus pneumonia. J Infect Dis 1991;163:631-633.

(27.) Docke WD, Simon HU, Fietze E, et al. Cytomegalovirus infection and common variable immunodeficiency. Lancet 1991;338:1597 (letter).

RELATED ARTICLE: Key Points

* The diagnosis of common variable immunodeficiency in this case was made on the basis of endoscopic and pathologic findings and was confirmed by the detection of severely diminished serum immunoglobulin levels in the setting of chronic recurrent sinopulmonary disease.

* If the patient's condition had been suspected earlier in the course of disease, later complications might have been avoided.

* Common variable immunodeficiency should be considered in all patients that present with recurrent bacterial infection; in addition, due to its potential to cause severe disease, cytomegalovirus should be included in the differential diagnosis of gastrointestinal symptoms in patients with common variable immunodeficiency so that further morbidity and mortality might be prevented.

RELATED ARTICLE: Case Report

A 66-year-old white woman presented with a 6- to 7-month history of watery diarrhea. She described intermittent diffuse abdominal cramping and 12 to 15 stools daily, including nocturnal symptoms. This was accompanied by anorexia and an involuntary 35- to 40-lb weight loss. She denied recent travel and had no known sick contacts. She did report being hospitalized for pneumonia 6 months before admission and treatment with antibiotics; however, the onset of her symptoms preceded this event. Her past medical history was significant for hypertension, gastroesophageal reflux disease (GERD), and recurrent sinusitis for which she received antibiotics 2 to 3 times yearly. Medications at admission included metoprolol, spironolactone, and loperamide. She denied use of tobacco, alcohol, or illicit drugs and had no significant occupational exposures. She lived in a rural area of Tennessee and drank well water at home. She denied fever or chills, hematemesis, hematochezia, or melena. Review of systems was otherwise positive for a chronic dry cough and sinus drainage, fatigue, depression, and generalized weakness.

Evaluation before presentation at our facility included stool studies for fecal leukocytes, Gram stain and culture, Clostridium difficile antigen, and ova and parasites, all of which were negative. She received an empiric course of metronidazole. A proton-pump inhibitor for GERD was discontinued, and a lactose-free diet was attempted without change in symptoms. Esophagogastroduo-denoscopy (EGD) with biopsies 5 months before arrival showed marked active gastritis as well as acute and chronic inflammation in the duodenum, with shortening of duodenal villi suspicious for celiac disease. A tissue transglutaminase level was obtained and was within normal limits, and she was placed on a gluten-free diet for 1.5 months without relief. Colonoscopy 1 month later showed ulceration of the sigmoid colon. Biopsy results showed acute and chronic inflammation with extensive cryptitis involving the cecum and ascending and sigmoid colon. Treatment for presumed ulcerative colitis was initiated with mesalamine. A computed tomographic (CT) scan was also performed at this time and showed a moderate-size fluid collection in the pelvis. At a follow-up visit, she complained of continued abdominal cramping and no improvement in diarrhea. An ultrasound of the abdomen was performed and was unremarkable. A hepatobiliary scan later showed delayed filling of the gallbladder and she underwent cholecystectomy at that time, 1 month before presentation at our facility. Symptoms persisted and she was treated with cholestyramine without improvement. She was seen in referral after this extensive workup and scheduled for outpatient endoscopy. In the interim she experienced nausea and emesis and was brought to the emergency department, where she was noted to be orthostatic and was admitted for fluid resuscitation.

At admission her temperature was 95.4[degrees]F. Her blood pressure was 80/50 mm Hg with a pulse rate of 109 beats/min. Her respiration was 20 breaths/min with oxygen saturation of 100% on room air. She weighed 98 lb, her height was 160 cm. She appeared cachectic and older than her stated age. Examination of her head, ears, eyes, nose, and throat (HEENT) revealed bilateral temporal wasting. She had no lymphadenopathy and no jugular venous distention. Her cardiac examination showed tachycardia but no extra heart sounds or murmurs. Her lungs were clear. Her abdominal examination revealed slightly hyperactive bowel sounds and mild tenderness to palpation diffusely, without guarding or rebound. She had 2+ pitting edema of her lower extremities. Rectal examination revealed external hemorrhoids and heme-positive stool.

Her admission laboratory values were significant for: serum sodium, 128 mEq/L; potassium, 4.6 mEq/L; chloride, 104 mEq/L; carbon dioxide level, 21 mmol/L; blood urea nitrogen, 20 mg/dL; creatinine, 0.7 mg/dL; and glucose, 97 mg/dL. Total protein was 3.1 g/dL and albumin was 1.3 g/dL. Remaining liver function tests were within normal limits. Urinalysis showed no evidence of proteinuria. Her white blood cell count was 5,700/[micro]L, hemoglobin 9.9 g/dL with a hematocrit of 30%, and mean corpuscular volume of 88. Iron studies revealed an iron level of 46 [micro]g/dl (normal, 50-150) and total iron-binding capacity (TIBC) of 67 [micro]g/dl (normal, 250-450). Her folate was 3.0 ng/mL (normal, 3.0-20.0) and her vitamin [B.sub.12] level was 1204 pg/mL (normal, 179-1132). She was admitted and started on intravenous fluids and total parenteral nutrition (TPN) to supplement her oral intake. Stool studies were again taken. Gram stain revealed no fecal white blood cells. Clostridium difficile antigen was negative, as were cultures for Cryptosporidia, Giardia, and three specimens sent for ova and parasites. Stool fecal fat was within normal limits. Anti-endomysial immunoglobulin A (IgA) antibody and anti-gliadin IgA and immunoglobulin G (IgG) antibodies were negative.

Upper and lower endoscopy performed shortly after arrival revealed edematous, pale mucosa throughout the entire gastrointestinal tract. EGD noted diffuse ulcerations in the duodenum. Colonoscopy showed a slightly deformed ileocecal valve, with scattered, superficial ulcers in the ileum. Biopsies were taken at several sites throughout the gastrointestinal tract. Specimens from the stomach revealed chronic atrophic gastritis with superimposed acute inflammation. The duodenum showed marked mucosal distortion with villous atrophy, ulceration, acute inflammation, and poorly formed granulomas (Fig. 1). Special stains for acid-fast bacilli and fungi were negative. A sample from the terminal ileum revealed distorted mucosa, with ulceration and granulation tissue (Fig. 2A). CMV was identified on immunoperoxidase stain (Fig. 2B). A random colon biopsy showed distorted colonic crypts, with loss of crypt parallelism, and acute inflammation. No plasma cells were identified on any of the tissue specimens.

Based on the findings of atrophic gastritis, marked villous atrophy, chronic colitis with inflammatory bowel disease-like features, and lack of plasma cells, the diagnosis of CVID was considered. Quantitative testing of serum immunoglobulins revealed markedly diminished levels of immunoglobulin M (IgM) (7 mg/dL, normal 60-263); IgG (7 mg/dL, normal 694 to 1,618); and IgA (<6 mg/dL, normal 68 to 378). Other tests included negative serologic tests for herpes simplex virus and human immunodeficiency virus. Her CD4 complement count was 186 cells/m[m.sup.3]. Epstein-Barr virus IgG antibodies were positive, while IgM was negative. She tested positive for CMV IgM antibody and negative for CMV IgG.

Based on this information, she was diagnosed with CVID with superimposed CMV infection and started intravenous treatment of immunoglobulin and ganciclovir. In addition, she underwent transfusion with 3 U packed red blood cells because of a decrease in hematocrit to 22%. She continued on TPN, including a regimen of thiamine as well as supplemental phosphorus to avoid refeeding syndrome. At examination and chest x-ray over the next several days, she developed increasing shortness of breath with evidence of new-onset pulmonary edema. An echocardiogram revealed severely depressed left ventricular systolic function, with a left ventricular ejection fraction of 5 to 15% and severe mitral regurgitation. Cardiac enzymes were negative and electrocardiogram showed no evidence of ischemia. Thyroid studies were normal. She developed worsening respiratory distress and was transferred to the medical intensive care unit. Because of her wishes to forgo mechanical ventilation, however, intubation was avoided, and she died shortly thereafter.

Elizabeth Stack, MD, Kay Washington, MD, George R. Avant, MD, and Glenn M. Eisen, MD, MPH