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`SEDITION
`
`scientific com-
`
`I
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`\
`
`j
`
`SEVENTEENTH EDITION
`
`V’-^'
`
`THE
`MERCK
`MANUAL
`OF
`DIAGNOSIS AND THERAPY
`
`MARKH
`
`Editors
`. BEERS. M.D., and ROBERT BERICOW, M.D.
`Senior Assistant Editors
`ROBERT M. BOGIN, M.D., and
`ANDREW). FLETCHER, M.B., B.Chir.
`Editorial Board
`Philip K. Bondy, M.D.
`Preston V. Dilts, ]r., M.D.
`Douglas A. Drossman, M.D.
`L. Jack Paling, M.D.
`Eugene P. Frenkel. M.D.
`Glen O. Gabbard, M.D.
`Robert A. Hoeckelman, M.D.
`Gerald L. Mandell, M.D.
`Fred Plum, M.D.
`G. Victor Rossi, Ph.D.
`Paul H. Tanser, M.D., F.R.C.P.(C)
`
`Published fay Merck Research Laboratories
`Division of Merck 8. Co., Inc.
`Whitehouse Station, N.J.
`
`1999
`
`■j:
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`Lt
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`*
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`\
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`
`i.)
`
`IPR2018-01714
`Celgene Ex. 2004, Page 1
`
`

`

`Editorial and Production Staff
`Executive Editor: Keryn A.G. Lane
`Senior Staff Editor: Susan T. Schindler
`Staff Editor: Julie Kostecky
`Staff Editor: Sandra J. Masse
`Production Editor: Debra G. Share
`Contributing Editor: Roger I. Schreck, M.D.
`Designer: Lorraine B. Kilmer
`Indexer: Susan Thomas, Ph.D.
`Textbook Production Coordinator: Diane C. Zenker
`Medical Textbook Coordinator: Dorothy A. Bailey
`Executive Assistant: Diane Gosner-Bobrin
`Publisher: Gary Zelko
`Advertising and Promotional Supervisor: Pamela J. Barnes
`
`Library of Congress Catalog Card Number 1-31760
`ISBN 0911910-10-7
`ISSN 0076-6526
`
`il-'
`
`i '’“-n
`
`Copyright 1999 by Merck & Co., Inc.
`All rights reserved. No part of this book may be reproduced or used in any
`form or by any means, electronic or mechanical, including photocopying, or
`by any information storage and retrieval system, without permission in writ­
`ing from the Publisher. Inquiries should be addressed to The Merck Manuals
`Department, P.O. Box 4, Merck & Co., West Point, PA 19486.
`Printed in the U.S.A.
`
`S
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`At,i
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`V
`
`IPR2018-01714
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`

`

`CONTENTS
`
`I'i, 1
`
`s
`
`r
`
`NUT
`
`r
`ND
`
`■ •.:n'
`
`Page
`xii
`xiii
`XV
`xvii
`xix
`
`1
`
`Tab
`
`NUT
`END
`Cl
`HEP
`MUS
`PUL
`ENT
`EYE
`DEN
`SKN
`HEM
`IMM
`INF
`NEU
`PSY
`CVS
`GU
`GYN
`PED
`PHY
`SPS
`Rx
`POl
`IND
`
`No.
`
`Section
`GUIDE FOR READERS
`abbreviations and symbols
`EDITORIAL BOARD
`CONSULTANTS
`CONTRIBUTORS
`NUTRITIONAL DISORDERS ..........................
`1
`ENDOCRINE AND METABOLIC DISORDERS
`2
`gastrointestinal disorders..........
`3
`hepatic AND BILIARY DISORDERS ,........
`4
`musculoskeletal disorders..........
`5
`PULMONARY DISORDERS................ • a • • ■
`6
`EAR, NOSE, AND THROAT DISORDERS ...
`7
`OPHTHALMOLOGIC DISORDERS......... . •
`8
`9 dental AND ORAL DISORDERS .............
`dermatologic DISORDERS ..... .
`10
`HEMATOLOGY AND ONCOLOGY ..........
`11
`IMMUNOLOGY; ALLERGIC DISORDERS .
`12
`INFECTIOUS DISEASES ..... .................. • ■ •
`13
`NEUROLOGIC DISORDERS ......................
`14
`PSYCHIATRIC DISORDERS................... -
`15
`CARDIOVASCULAR DISORDERS..... .......
`16;
`GENITOURINARY DISORDERS ................
`17
`GYNECOLOGY AND OBSTETRICS..........
`18
`19 PEDIATRICS ............................................
`DISORDERS DUE TO PHYSICAL AGENTS
`20
`21 SPECIAL SUBJECTS ......... ................... .
`CLINICAL PHARMACOLOGY ................
`22
`POISONING
`23
`INDEX
`
`hybfv
`
`•11
`
`1
`63
`221
`343
`407
`509
`657
`,. 699
`745
`777
`..... 847
`..... 1001
`1085
`1341
`1503
`1599
`1801
`1923
`2071
`2433
`2469
`2555
`2619
`2657
`
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`

`

`MA CtLL DYSCRASIAS
`
`Especially carcinomas of tho
`; , prostate, kidney, GI tract
`j breast, and biliary tree ’
`! Chronic cholecystitis, osteo­
`myelitis, TB, pyelonephritis
`. HA
`. ’
`
`4
`
`)
`
`Lichen myxedematosus, liver
`dis-
`i-r ease, thyrotoxicosis, pemicin~
`L anemia, myasthenia gravis ^
`I' Gaucher’s disease, familial’
`I hypercholesterolemia, Kaposi
`1 sarcoma
`8
`Incurs in apparently healthy
`Per-
`■: sons; age-related incidence
`
`;G, IgA, light chains (Bence
`Jones) only, IgD, IgE, non-
`secretory
`||sually light chains (Bence
`[Jones) only, but occasionaUy
`p,intact immunoglobulin mole-
`p cules (IgG, IgA, IgM, IgD) '
`bG heavy chain (y-chain) disease
`heavy chain (a-chain) disease
`P heavy chain (p,-chain)
`^••isease .
`heavy chain (B-chain) disease
`pciated with drug hypersensi-
`wly, vual infections, and
`?art surgery
`
`or other lymphoproliferative
`tufJ® clinically distinct
`motherplasmacelldyscra-
`paiymphomatous disease.
`Men are affected
`Pomen; the median
`age is
`Infestations of macro-
`KiBH ™ amount of
`|somp^f®®°g^°bulin circu-
`Ltih5.*ese monoclonal
`to au-
`|f“'oidfactors)ortol
`an-
`
`and Signs
`SympH”’’®
`Most patients are asymptomatic, but many
`sent with manifestations of the hypervis-
`jty syndrome: fatigue, weakness, skin
`mucosal bleeding, visual disturbances,
`Sache, and other changing neurologic
`manifestations. When predominant, cardio-
`nulmonai-y abnonnalities are due to circu-
`Loiy inipainnent caused by an increased
`plasma volume. Cold sensitivity or Ray­
`naud’s phenomenon may be due to a cryo­
`globulin or cold agglutinin. Recurrent bac­
`terial infections are a rntyor problem in some
`patients.
`Examination may disclose generalized
`lymphadenopathy, puipura, hepatospleno-
`megaly, and marked engorgement and local­
`ized narrowing of retinal veins, which resem­
`ble sausage links. Amyloidosis occurs in 5%
`of patients.
`
`CHAPTER 140 - PLASMA CELL DYSCRASIAS / 965
`The hyperviscosity syndrome can be di­
`agnosed by the funduscopic finding of retinal
`veins that resemble sausage links. Retinal
`hemorrhages, exudates, microaneuiysms,
`and papilledema indicate late stages. Rela­
`tive serum viscosity is usually >4.0 (normal,
`1.4 to 1.8) in patients with the hyperviscosity
`syndrome.
`Prognosis and Treatment
`The course is variable, but macroglobulin-
`emia tends to be more benign than is mye­
`loma. The median survival is about 5 to 7 yr.
`Age > 60 yr, anemia, and cryoglobulinemia
`are associated with shorter survival.
`Often, patients require no treatment for
`many years. If hyperviscosity is present, ini­
`tial management consists of plasmapheresis,
`which rapidly reverses bleeding and
`neuro-
`logic abnormalities caused by high IgM lev­
`els. Plasmapheresis often needs to be
`re-
`peated.
`Long-term treatment vrtth oral alkylating
`drugs, usually chlorambucil, may be
`neces-
`sary in some patients; however, bone mar­
`row toxicity (see below under Multiple My­
`eloma) can occur. Chlorambucil 0.03 to 0.09
`mg/kg/day or pulses of 0.26 mg/kg/day for
`4 days q 4 to 6 wk may be used. Melphalan
`or cyclophosphamide, as given for multiple
`myeloma, are possible alternatives, and oral
`prednisone (1 mg/kg/day for 4 days q 4 to 6
`wk) may be added. Recent results with the
`purine analogs fludarabine and 2-chloro-
`deoxyadenosine have been encouraging and
`offer alternatives to patients unresponsive to
`standard oral alkylating drugs. Interferon
`re-
`duces M protein in some patients.
`
`Diagnosis
`Most diagnoses of monoclonal gammopa-
`thy ar-e preceded by incidental discovery of
`elevated serum total protein or anemia. The
`diagnosis is established by demonstrating a
`typical M spike on serum protein electropho­
`resis that proves to be IgM by Immunoelec­
`trophoresis or immunoflxation.
`Moderate anemia, marked rouleaux for­
`mation, and a very high ESR are typical.
`Leukopenia, relative lymphocytosis, and
`thrombocytopenia occasionally occur. Cryo­
`globulins, rheumatoid factor, or cold agglu­
`tinins may be present; if the latter are
`pres­
`ent, the direct Coombs’ test usually is
`positive. Various coagulation and platelet
`function abnormalities may occur. Results of
`routine blood studies may be spurious if a
`MULTIPLE MYELOMA
`ciyoprotein is present or if viscosity is mark­
`edly increased. Normal immunoglobulins rpiacrv, n u hy i
`.
`are decreased in 1/2 of patients.
`(Plasma Cell Myeloma; Myelomatosis)
`Immunoelectrophoretic studies of con- ^ P'^'ogressive neoplastic disease charact&r-
`centrated urine frequently show a mono-
`by marrow plasmacytomas (plasma
`clonal light chain (usually k), but gross Bence
`tumors) and overproduction of an in-
`Jonesproteinuriais unusual. X-rays of bones
`monoclonal immunoglobulin (IgG,
`may show osteoporosis, but lytic lesions are
`^dD, or IgE) or Bence Jones protein
`rare. Bone marrow studies show a variable in-
`monoclonal k or X light chains).
`mac^^tTlZ^hnf^’
`myelomais often associated with
`macytoid lymphocytes. PAS-positive mate- multiple osteolytic lesions, hypercalcemia
`damage, and leased sus-
`Srion
`increased. In ceptibility to bacterial infections; production
`frequently of normal immunoglobulin is impaired. The
`well-differentiated or incidence is estimated at 2 to 3/100,000 per-
`plasmacytic lymphocytic lymphoma.
`sons, the male:female ratio is 1.6:1, and most
`
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`i
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`966 / SECTION 11 - HEMATOLOGY AND ONCOLOGY
`patients are > 40 yr. The prevalence in
`or recurrent bacterial infectiorrs are th
`blacks is twice that in whites.
`common presentations. Pathologic h
`and vertebral collapse are common-
`Etiology and Pathogenesis
`ter may lead to spinal cord compressi
`The etiology is unknown. A relationship is
`paraplegia. Renal failiue (myeloma Idn
`suggested by finding Kaposi’s sarcoma-
`may be caused by extensive cast forin
`associated herpes virus in the dendritic cells
`in the renal tubules, atrophy of tubula^*^°f'
`cultured from myeloma patients. This virus
`theMal cells, and interstitial fibrosis. An
`encodes an interleukin-6 homologue; human
`sometimes with weakness and fatigue^'^*^’
`interleukin-6 promotes myeloma growth and
`dominates in some patients, and a few'h**^^
`stimulates resorption of bone.
`manifestations of the hyperviscosity
`The specific cell of origin is unknown.
`drome (see under Macroglobuline^'
`Analysis of immunoglobulin gene sequences
`above). Lymphadenopathyandhepatosn]
`en-
`and cell surface markers suggests malignant
`omegaly are unusual.
`^
`transformation of a post-germinal center
`Diagnosis
`cell.
`In the patient with a serum M protein an
`Pathology
`one of three additional findings fulfills crit<f
`Diffuse osteoporosis or discrete osteolytic
`ria for the diagnosis of myeloma: sheets or
`lesions develop, usually in the pelvis, spine,
`clusters of marrow plasma cells, osteolytic
`ribs, and skull. Lesions are due to bone re­
`lesions (without evidence of metastatic car­
`placement by expanding plasmacytomas or
`cinoma or granulomatous disease), or Bence
`a factor secreted by malignant plasma cells
`Jones proteinuria > 300 mg/24 h.
`(osteoclast-activating factor). The osteolytic
`Blood tests show a normocytic normo­
`lesions are usually multiple but occasionally
`chromic anemia with rouleaux formation
`are solitary intramedullary masses. Extraos-
`The WBC and platelet counts usually are nor­
`seous plasmacytomas are unusual but may
`mal. The ESR is often markedly elevated
`occur in any organ, especially the upper res­
`sometimes > 100 mm/h, and BUN, serum
`piratory tract.
`creatinine, and serum uric acid are fre­
`Plasmacytomas produce IgG in about
`quently elevated. A low anion gap is some­
`66% of myeloma patients and IgA in about
`times present. Hypercalcemia is found at di­
`20%; of these IgG and IgA patients, 40% also
`agnosis in about 10% of patients. The serum
`have Bence Jones proteinuria. Light chain
`level of P2-microglobulin is frequently ele­
`myeloma is found in 16 to 20% of patients;
`vated and correlates with myeloma cell
`their plasma cells secrete only free mono­
`mass.
`clonal light chains (k or \ Bence Jones pro­
`Proteinuria is common because of ex­
`tein), and an M spike is usually absent on
`cess synthesis and secretion of free mono­
`serum electrophoresis. Patients with the
`clonal light chains. Chemical paper strip
`light chain subgroup tend to have a higher
`tests of urine do not reliably detect Bence
`incidence of lytic bone lesions, hyper­
`Jones protein, and the heat test is often mis­
`calcemia, renal failure, and amyloidosis than
`leading, but sulfosalicylic acid and toluene
`do other myeloma patients. IgD myeloma ac­
`sulfonic acid are useful screening tests. Sig­
`counts for about 1% of cases; serum levels
`nificant albuminuria is rare in myeloma; its
`are often relatively low, and marked Bence
`presence suggests coexisting amyloidosis or
`Jones proteinuria (80 to 90% type \) is char­
`light chain deposition disease.
`acteristic. Only a few cases of IgE myeloma
`Seriun protein electrophoresis shows a
`have been reported. Nonsecretoiy myeloma
`taU, narrow, homogeneous M spike in about
`(no identifiable M component in serum or
`80% of patients; the mobility of the M spike
`urine) is very rare (< 1 % of cases).
`may lie anywhere from the a2 to the slow -y
`Amyloid deposits (see Ch. 18) occur in
`region. The remaining 20% of patients syn­
`10% of myeloma patients and are. especially
`thesize only free monoclonal light chains
`likely in those with Bence Jones proteinuria.
`(Bence Jones protein), and their serum elec­
`trophoretic patterns display hypogamma­
`Symptoms and Signs
`globulinemia without an M spike. However,
`Persistent unexplained skeletal pain (es­
`in essentially all patients with light chain
`pecially in the back or thorax), renal failure.
`myeloma, a homogeneous M spike is demon-
`
`tA
`I W
`
`i I
`
`I
`
`X
`
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`I
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`>
`
`C-;
`
`tX;
`
`W.
`
`IK
`
`(>-
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`K ■
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`1&:
`
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`
`CHAPTER 140 - PLASMA CELL DYSCRASIAS / 967
`have little evidence of impaired renal func­
`strable on protein electrophoresis of concen­
`tion if they are well hydrated (urine output
`trated urine. Immunoelectrophoresis or im-
`> 2000 mL/day).
`munofixation using monospecific antisera
`Prednisone 60 to 80 mg/day po is useful
`identifies the immunoglobulin class of the M
`for controlling hypercalcemia; pamidronate
`spike in senim or urine.
`may be helpful in refractory cases (see
`X-rays of the bones may show typical
`above). Although most patients do not re­
`punched-out lytic lesions or diffuse osteo­
`quire allop\irinol, a dose of 300 mg/day po
`porosis. Osteoblastic lesions are rare, and
`controls hyperuricemia. Antibiotics are in­
`thus radionuclide bone scans usually are
`dicated for documented bacterial infection,
`not helpful. MRI may be useful, particularly
`but prophylactic use is not recommendedi
`in predicting outcome in patients with early-
`Most patients experience infections only
`stage disease.
`during chemotherapy-induced neutropenia.
`Bone marrow aspiration and biopsy
`Prophylactic IV immunoglobulin has been
`usually .show increased numbers of plasma
`shown in some studies to reduce the risk of
`cells at various stages of maturation; rarely
`infections. However, it should be reserved
`is the numberpf plasma cells nomral. Plasma
`for select patients with recurrent infections.
`ceil'morphology does not correlate with the
`Transfusion of packed RBCs is indicated for
`class of immunoglobulin synthesized. Al­
`symptomatic anemia. Recombinant ersdh-
`though sheets and clusters of plasma cells
`ropoietin is very effective in reversing the
`are diagnostic of marrow tunrors, myeloma
`anemia, especially in patients with renal dys­
`is a patchy disease, and often only modest
`function; however, its use should be limited
`nonspecific plasmacytosis is observed ini­
`to patients for whom chemotherapy does not
`tially.
`:
`raise Hb.
`Prognosis and Treatment
`Chemotherapy: Response to chemother­
`apy is indicated by decreases in serum or
`The disease is progressive, but good man­
`urine M protein. Conventional chemother­
`agement improves the quality and duration
`apy rarely eliminates M protein; however,
`of life. About 60% of patients treated show
`objective improvement (a > 60% reduction
`objective improvement. Median survival is
`in serum or urine M protein) often follows
`about 2.6 to 3 yr, but this varies according to
`use of oral alkylating drugs (melphalan or
`the extent of disease at diagnosis, adequacy
`cyclophosphamide). Median survival may be
`of supportive measures, and response to
`extended three- to sevenfold.
`drugs. At diagnosis, high levels of M protein
`Prednisone (1 mg/kg/day for 4 days q 4 to
`in serum or urine, elevated serum Pa-micro-
`6 wk) or another glucocorticosteroid should
`globulin levels, diffuse bone lesions, hyper­
`be used with melphalan or cyclophospha­
`calcemia, anemia, and renal failure are un­
`mide. Glucocorticosteroids may be used
`favorable prognostic signs.
`alone to treat patients with newly diagnosed
`Maintenance of ambulation is vital for pro­
`tection from hypercalcemia and bone qual­
`myeloma.
`Melphalan may be given intermittently
`ity. Analgesics and palliative doses of radio­
`(0.26 mg/kg/day for 4 days q 4 to 6 wk).
`therapy (18 to 24 Gy) administered to
`About 2 wk after administration, a WBC
`localized areas of symptomatic bone in­
`count must be obtained at nadir; if WBCs are
`volvement reUeve pain significantly. How­
`> 3000/p-L, the dose may be inadequate.
`ever, radiotherapy may impair the patient’s
`Prednisone given intennittently (1 mg/kg/
`ability to receive cytotoxic doses of systemic
`day for 4 days q 6 wk) may improve response
`chemotherapy. All patients should receive
`to melphalan. Cyclophosphamide (200 mg/
`pamidronate (90 mg/mo IV), which reduces
`day for 5 to 7 days, then 60 to 100 mg/day for
`skeletal complications and lessens bone pain
`maintenance) appears to be as effective as
`and the need for analgesics. This treatment
`melphalan. Because leukopenia and thro­
`may also improve survival.
`mbocytopenia may develop with use of these
`Adequate hydration is essential. {Dehy­
`drugs, WBC and platelet counts must be
`dration before intravenous dye load may
`closely monitored.
`precipitate acute oliguric renal failure in
`Acute nonlymphocytic leukemia or mye­
`patients with Bence Jones proteinuria.)
`lodysplasia follows in a minority of respond­
`Even patients with prolonged massive Bence
`ing patients and is likely related to length of
`Jones proteinuria (a 10 to 30 g/day) may
`
`I
`
`rGU
`
`rn
`1Lll
`
`I
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`I
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`14
`
`fPSY
`15
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`r/s
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`16
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`iS
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`i
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`y (
`
`II
`
`y/-
`
`968 / SECTION 11 - HEMATOLOGY AND ONCOLOGY
`exposure to mutagenic agents (alkylating
`drugs, irradiation). Thus, care must be taken
`to ensure that patients receive therapy for
`the shortest duration needed. Continuation
`of chemotherapy beyond this point has not
`been shown to improve survival.
`High-dose therapy, ie, the use of more
`aggressive multidrug regimens requiring he­
`matopoietic support, appears promising, al-
`mough improvement in overall survival has
`been difficult to demonstrate in randomized
`tnals. Because alkylating drugs should be
`avoided in high-dose therapy (they damage
`hematopoietic stem cells), infusional vin-
`cnshne and doxorubicin with oral dexa-
`methasone should be considered before
`transplantation. High-dose therapy followed
`by autologous bone marrow transplant in pa­
`tients who previously received l_
`several
`courses
`of conventional chemotherapy
`was
`shown to improve remission rates and
`sur-
`vival in one study.
`Autologous peripheral stem cell sup­
`port has largely replaced bone marrow
`transplantation for myeloma patients under­
`going myeloablative chemotherapy. This
`procedure should be considered in patients
`< 70 yr with stable
`„
`,
`or responsive disease
`after treatment with several courses of con­
`ventional chemotherapy. However
`treat-
`ment-related mortality is high.
`Maintenance therapy has been tried
`wdh nonchemotherapeutic drugs, including
`i^erferon, which prolongs remission but has
`little effect on overall survival. Glucocorti-
`costeroids are being evaluated.
`
`tural mutations. The clinical picture is n,
`like lymphoma than multiple myeloma
`
`IgA Heavy Chain (a-Chain)
`Disease
`IgA heavy chain disease is the most con,
`mon heavy chain disease and usuallv?''
`pears between ages 10 and 30 yr. It is „
`graphically concentrated in the Middle I!®"
`and IS closely related to Mediterranean
`phoma or immunoproliferative small iJo
`tmM disease. The clinical picture is strikin„t
`uniform: almost all patients present with If
`fose abdominal lymphoma and malabson!.
`bon syndrome. Histopathologic examinati^
`discloses villous atrophy and massive infif
`tration of the lamina propria of the intestSi
`by lym^ocytes, plasma cells, or immurm '
`blasts. The cellular infiltrate may be plen-
`moiphic and not overtly malignant by histo
`pathologic criteria. Mesenteric lymph nodes
`may show a similar lymphoplasmacytic inffl
`tration, but peripheral nodes, marrow, liver
`and spleen usually are not involved. Osteo’
`lytic lesions are not seen on bone x-ravs A
`discrete M spike may not be observed on
`serum protein electrophoresis; often, there
`IS a broad band in the oig and p regions or a
`decreased 7 fraction. Immunochemical dii
`agnosis requires the detection of an abnor­
`mal component on immunoelectrophoresis
`reactive with anti-IgA antiserum but not with
`anti-hght chain antiserum. The abnormal
`protein is usually present in intestinal secre­
`tions and may be found in concentrated
`unne. Berlce Jones proteinuria is absent
`Treatment is with corticosteroids, cyto­
`toxic drugs, and broad-spectrum antibiotics'
`prolonged remissions have been reported In
`view of the responses to antibiotics alone
`and the peculiar geographic incidence of the
`disorder, oi-chain disease may represent an
`aberrant unmune response to a parasite or
`other microorganism. A respiratoiy-tract
`form of the disease has been reported rarely.
`
`IgG Heavy Chain (7-Chain)
`Disease
`More than 100 cases have been reported,
`pnmarily in elderly men and a few in chil-
`Men. Associated chronic disorders include
`HA, bjogren’s syndrome, SLE, TB, myasthe­
`nia gravis, hypereosinophilic syndrome, au-
`
`■O
`
`'■.L
`
`I
`
`V
`
`4
`
`-4
`■4
`
`HEAVY CHAIN DISEASES
`Neoplastic plasma cell dyscrasias charac­
`terized by overproduction of monoclonal
`immunoglobulin heavy chains.
`In most plasma cell dyscrasias, M proteins
`are structurally similar to nonnal antibody
`molecules. In contrast, in hea'vy chain dis-
`e^es, incomplete monoclonal immunoglob-
`ulms (true paraproteins) are produced. Ab­
`normal lymphocytes or plasma cells secrete
`the vanous heavy chain components (alpha
`[a], gamma [7], mu [p,], or delta [8]) without
`light chains, (e Heavy chain disease has not
`been described.) Most heavy chain proteins
`are fragments of their normal counterparts
`TOth mtemal deletions of variable length'
`these deletions appear to result from
`struc-
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`CHAPTER 162 - VIRAL DISEASES / 1295
`For immunosuppressed patients with her­
`pes zoster, acyclovir IV is recommended at
`a dosage of 10 mg/kg q 8 h for 7 days for
`adults and 600 mg/m^ q 8 h for 7 days for
`children a 1 yr (30 mg/kg/day in 3 divided
`doses for children < 1 yr). Oral famciclovir,
`valacyclovir, and acyclovir are all used for
`treatment of herpes zoster in immunocom­
`petent patients, and data indicate they may
`decrease postherpetic neuralgia as well as
`accelerate healing. Famciclovir and valacy­
`clovir have better bioavailability with oral
`dosing than acyclovir.
`To try to prevent neuralgia, corticoste­
`roids have been used, but the data are con­
`troversial and such treatment is not recom­
`mended. Management of postherpetic
`neuralgia can be particularly difficult and
`may include tricyclic antidepressants.
`For treatment of ophthalmic herpes zos­
`ter, see Ch. 96.
`CYTOMEGALOVIRUS INFECTION
`(Cytomegalic Inclusion Disease)
`Various infections caused by cytomegalo­
`virus, occurring congenitally, postna-
`tally, or at any age, ranging from incon­
`sequential silent infection to disease
`manifested by fever, hepatitis, pneumo­
`nitis, and, in newborns, severe brain
`damage, stillbirth, or perinatal death.
`(See also Congenual and Perinatal Cyto­
`megalovirus Infection under Neonatal In­
`fections in Ch. 260.)
`Etiology and Epidemiology
`Transmission of cytomegalovirus (CMV)
`is through blood, body fluids, or transplanted
`organs. Infection may be acquired transpla-
`centally or during birth. Cytomegalic inclu­
`sion disease refers to the intranuclear inclu­
`sions found in enlarged infected cells.
`Prevalence in the general population in­
`creases gradually with age; 60 to 90% of
`adults have had CMV infection. Lower so­
`cioeconomic groups tend to have a higher
`prevalence.
`Symptoms and Signs
`Congenital infection may be manifested
`only by cytomegaloviruria in an otherwise
`apparently normal infant. At the other ex­
`treme, CMV infection may cause abortion,
`stillbirth, or postnatal death from hemor­
`rhage, anemia, or extensive hepatic or CNS
`
`0
`
`Chai'acteristic crops of vesicles on an ery­
`thematous base then appear, following the
`cutaneous distribution of one or more atfja-
`cent dermatomes. The involved zone is usu­
`ally hyperesthetic, and pain may be severe.
`Eruptions occur most often in the thoracic
`or liimbtu’ region and are unilateral. Lesions
`usually continue to form for about 3 to 6 days.
`Herpes zoster may disseminate to other
`' regions of the skin and to visceral organs,
`especially in immunosuppressed patients.
`Fewer than 4 % of patients with herpes zos­
`ter experience recurrence; most patients re­
`cover, but many, particularly the elderly,
`have postherpetic neuralgia, which may per­
`sist for months or years. The pain of post­
`herpetic neuralgia may be sheirp and inter­
`mittent or constant and may be debilitating.
`Geniculate zoster (Ramsay Hunt’s syn­
`drome) results from involvement of the ge­
`niculate ganglion. Pain in the ear and facial
`paralysis occur on the involved side. A vesic­
`ular eruption occurs in the external auditory
`canal, and taste may be lost in the anterior
`two thirds of the tongue (see also H erpes Zos­
`ter Oticus in Ch. 86).
`Ophthalmic herpes zoster (see also in
`i Ch. 96) follows involvement of the gasserian
`' ganglion, with pain and a vesicular eruption
`in the distribution of the ophthalmic division
`of the 6th nerve. Vesicles on the tip of the
`nose indicate involvement of the nasociliary
`branch of the 6th nerve and may predict the
`. occun'ence of comeal lesions. However, eye
`1 involvement may occur in the absence of le-
`• sions on the tip of the nose. An ophthalmol­
`ogist should be consulted to help evaluate
`and prevent invasive eye disease.
`Diagnosis
`Diagnosis is difficult in the preemption
`stage but is readily made after the vesicles
`appear. The Tzanck preparation shows mul-
`tinucleate giant cells for both varicella-zos­
`ter vims and HSV. Antigen detection from a
`biopsy can be useful. Pleurisy, trigeminal
`neuralgia. Bell’s palsy, and chickenpox (in
`children) must be differentiated. HSV may
`produce nearly identical zosteriform lesions,
`but unlike herpes zoster, HSV tends to recur.
`The vimses can be differentiated serologi­
`cally and by cultme.
`Treatment
`Locally applied wet compresses are sooth­
`ing, but analgesics are often necessary.
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`1296 / SECTION 13 - INFECTIOUS DISEASES
`damage (see Congenital and Perinatal Cy­
`tomegalovirus Infection under Neonatal In­
`fections in Ch. 260).
`Acquired infections are often asymp­
`tomatic, whether acquired postnatally or
`later in life. An acute febrile illness, termed
`cytomegalovirus mononucleosis or cyto­
`megalovirus hepatitis, may occur.
`In immunosuppressed patients, CMV is
`a major cause of morbidity and mortality.
`Disease often results from reactivation of
`latent virus infection. Patients may have
`pulmonary, Gl, or CNS involvement. In the
`terminal phase of AIDS, CMV infection
`commonly causes retinitis and ulcerative
`disease of the colon or esophagus (see Ch.
`163).
`Postperfusion/posttransfusion syn­
`drome can develop in a normal host 2 to 4
`wk after transfusion with fresh blood con­
`taining CMV. It is characterized by fever last­
`ing 2 to 3 wk, hepatitis of variable degree,
`splenomegaly, and a characteristic atypical
`lymphocytosis resembling that of infectious
`mononucleosis. Disease generally resem­
`bles spontaneous CMV mononucleosis, al­
`though splenomegaly is more common.
`Diagnosis
`Especially in the immunocompromised
`host, CMV may be isolated from urine, other
`body fluids, or tissues. However, CMV can
`be excreted for months or years after infec­
`tion without causing active disease, and a
`positive CMV culture must be interpreted
`with regard to the particular host and dis­
`ease manifestation. Biopsy showing CMV-
`induced pathology is often important in
`demonstrating invasive disease. Promising
`techniques for rapid diagnosis include dem­
`onstrating CMV antigens or DNA.
`Congenital infection must be differenti­
`ated from bacterial, viral (eg, rubella), and
`protozoan (eg, toxoplasmosis) infections.
`Diagnosis in infants is best made by urine
`culture.
`CMV mononucleosis must be differenti­
`ated from viral hepatitis, Epstein-Barr virus,
`and other causes of mononucleosis-like syn­
`dromes. The absence of pharyngitis and a
`negative heterophil antibody test help distin­
`guish primary CMV mononucleosis from
`Epstein-Barr virus infection, but fever and
`atypical lymphocytosis are typical of both
`syndromes. Seroconversion can be demon­
`strated by development of CMV antibodies.
`
`Treatment
`Ganciclovir IV is used to treat CMV reti­
`nitis and for prophylaxis of CMV disease in
`transplant recipients at risk for developing
`CMV disease. Oral ganciclovir is used for pr^^
`vention of CMV disease in HIV patients and
`for maintenance therapy in certain patients
`with CMV retinitis. Ganciclovir ocular hn-
`plants provide prolonged treatment for reti­
`nitis but do not provide systemic treatment
`Foscamet and cidofovir are also used for
`CMV retinitis in patients with AIDS. Intra­
`ocular injections of ganciclovir or foscamet
`have been performed at times, primarily as
`salvage therapy. Anti-CMV agents are used
`to treat nonretinitis severe CMV disease, but
`response to treatment is somewhat less con­
`sistent. Passive CMV immune globulin has '
`had some success at reducing disease in cer­
`tain seronegative transplant recipients (see
`also Ch. 164). Ganciclovir plus immune glob­
`ulin has been used to treat CMV pneumonia
`in bone marrow transplant patients.
`CENTRAL NERVOUS
`SYSTEM VIRAL DISEASES
`RABIES
`(Hydrophobia)
`An acute infectious disease of mammals,
`especially carnivores, characterized by
`CNS pathology leading to paralysis and
`death.
`Etiology and Epidemiology
`Rabies is caused by a neurotropic vims '
`often present in the saliva of rabid animals.
`Isolates of rabies vims collected from differ­
`ent animal species and from different parts
`of the world are distinct.
`Rabid animals trsmsmit the infection by
`biting animals or humans. Rabies is rarely '
`transmitted from infected saliva to a mucous
`membrane or skin abrasion. Other rare cases
`of respiratory infections followed exposure
`in the laboratory and from the atmosphere
`of a bat-infested cave.
`Worldwdde, rabid dogs still present the
`highest risk to hiunans. Rabies in dogs is
`prevalent in Latin America, Africa, and Asia.
`In the USA, where vaccination has largely
`eliminated canine rabies, bites of infected !
`wild animals, especially bats, have caused
`most of the infrequent cases of hiunan rabies
`since 1960.
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