Nej m Cpc 1109276

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case records of themassachusetts general hospital

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 366;25 nejm.org june 21, 2012 2409

Founded by Richard C. CabotNancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate EditorJo-Anne O. Shepard, m.d.,Associate Editor Alice M. Cort, m.d.,Associate EditorSally H. Ebeling,Assistant Editor Christine C. Peters, Assistant Editor

From the Departments of Pediatrics(E.A.C., H.S.W.), Medicine (H.S.W.,M.L.-R.), Radiology (R.S.), and Pathology(M.L.), Massachusetts General Hospital;and the Departments of Pediatrics(E.A.C., H.S.W.), Medicine (H.S.W.,M.L.-R.), Radiology (R.S.), and Pathology(M.L.), Harvard Medical School bothin Boston.

N Engl J Med 2012;366:2409-19.Copyright 2012 Massachusetts Medical Society.

PRESENTATION OF CASE

A newborn boy was admitted to the neonatal intensive care unit (NICU) of this hos-pital because of respiratory distress.

The patient was born at a gestational age of 29 weeks at another hospital bycesarean section for breech presentation, premature labor, and rupture of mem-branes of approximately 2 hours duration. He weighed 1275 g and appeared vigor-ous, with spontaneous respirations; the 1-minute and 5-minute Apgar scores were7 and 9, respectively. Shortly thereafter, subcostal retractions developed. Analysisof umbilical arterial blood revealed a pH of 7.35, a partial pressure of oxygen of47 mm Hg, and a partial pressure of carbon dioxide of 22 mm Hg. Continuous positive

airway pressure (CPAP) was administered, and he was transferred to the nursery.The temperature was 37.2C under radiant heat, the blood pressure 58/44 mm Hg,the pulse 119 beats per minute, and the oxygen saturation 94 to 96% while thepatient was breathing 50% oxygen with CPAP; the blood glucose level was 72 mg perdeciliter (4.0 mmol per liter).

Transfer to this hospital was arranged; 1 hour after birth, the MassGeneral Hos-pital for Children NICU transport team arrived at the other hospital. On examination,the patient was nondysmorphic and the skin was pink and well perfused. There weremoderate subcostal retractions, shallow respirations, and bronchial breath soundsthat were slightly diminished in intensity; the remainder of the examination wasnormal for the gestational age. The trachea was intubated and assisted ventilationwas begun; oxygen was administered to maintain hemoglobin saturation levels in

the mid-90s percentage range. Proper position of the endotracheal tube was con-firmed with the use of radiography. The blood glucose level decreased to 34 mg perdeciliter (1.9 mmol per liter). A peripheral intravenous catheter was placed, and aninfusion of 10% glucose was begun; the glucose level rose to 134 mg per deciliter(7.4 mmol per liter). He was transported by ambulance to this hospital and admit-ted to the NICU.

The patients mother was 24 years of age, gravida 4, para 1 to 2, with a history ofintravenous drug abuse, hepatitis C virus infection, and bipolar disorder; 6 monthsearlier she had had a methicillin-resistantStaphylococcus aureus skin infection. She

Case 19-2012: A Premature Newborn Boywith Respiratory Distress

Elizabeth A. Catlin, M.D., H. Shaw Warren, M.D., Randheer Shailam, M.D.,Manuella Lahoud-Rahme, M.D., and Madelyn Lew, M.D.

The New England Journal of Medicine

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Copyright 2012 Massachusetts Medical Society. All rights reserved.

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n engl j med 366;25 nejm.org june 21, 20122410

had received regular prenatal care and lived in ashelter. Medications during pregnancy includedmethadone, clonazepam, clonidine, and iron sup-plements. The maternal blood type was A, Rh-positive, with negative antibody screening. Pre-natal testing for hepatitis C virus antibody waspositive; testing for syphilis, the human immu-

nodeficiency virus, hepatitis B virus, and gono-coccal and chlamydial infections was negative.The newborn had a healthy half-sibling; therewas no family history of genetic abnormalities.

On examination in the NICU, the patientstemperature was 37.6C, the blood pressure60/30 mm Hg, the pulse 174 beats per minute(normal, 80 to 180), and the respiratory rate 56breaths per minute (normal, 30 to 60). He at-tempted to cry around the endotracheal tube;breath sounds were decreased bilaterally. Heartsounds were normal, without murmurs; the ex-

tremities were warm and well perfused; testeswere in the inguinal canals; the skin was ruddyand thin, with visible veins; no plantar creaseswere present; and there was no breast tissue. Hemoved all extremities, with resting posture inextension; the remainder of the examination wasnormal for his gestational age. Blood levels ofphosphorus, magnesium, total and direct biliru-bin, and creatinine were normal, as was the aniongap; other results are shown in Table 1. Chestradiographs showed diffuse, f ine granular opac-ities and mild perihilar linear opacities bilater-ally, features thought to be consistent with therespiratory distress syndrome of the newborn.Surfactant, caffeine, ampicillin, and gentamicinwere administered. An umbilical venous catheterwas placed.

On the patients second day of life, the neona-tal abstinence syndrome developed (characterizedby tremors, agitation, poor sleeping, and franticbehavior); screening of the urine for illicit drugswas negative. Morphine was administered, result-ing in improvement. Radiographs showed im-

provement in the pulmonary opacities. The tracheawas extubated, and nasal CPAP was administeredtransiently. Results of testing conducted by theMassachusetts newborn screening program werenormal. Culture of blood drawn on admissionwas sterile, and the administration of antibioticagents was stopped.

During the patients third day of life, when hewas still in the NICU, a systolic ejection murmur

was heard, respiratory distress recurred, and re-spiratory acidosis developed (Table 1). The tra-chea was reintubated, and a radiograph showedchanges consistent with pulmonary edema andan increase in the size of the cardiac silhouette.Echocardiography revealed normal cardiac struc-tures, normal ventricular function and thickness

(left ventricular ejection fraction [LVEF], 69%), apatent ductus arteriosus (2.3 mm) with left-to-right shunting, estimated right ventricular sys-tolic pressure of 55 mm Hg with systemic sys-tolic pressure of 58 mm Hg, a patent foramenovale, and no pericardial effusion. The adminis-tration of ampicillin and gentamicin was re-started, and ibuprofen was added. Feedings ofpasteurized human milk, administered by ga-vage, were started. Ultrasonography of the brainrevealed grade 1 hemorrhage into the germinalmatrix bilaterally, with normal brain parenchy-

ma. The patients respiratory status improved,clinical evidence of the patent ductus arteriosusresolved, and the trachea was extubated on thepatients fifth day of life.

On the sixth day of life, the patients work ofbreathing increased suddenly and mottled skindeveloped; the trachea was reintubated, and stressdoses of hydrocortisone, oxacillin, gentamicin,and intravenous saline were administered. Echo-cardiography revealed a small, concentric pericar-dial effusion, no evidence of tamponade, mark-edly thickened ventricular walls, near obliterationof right and left ventricular cavities, and underfill-ing of both ventricles; biventricular systolic func-tion was preserved (LVEF, 61%). A radiographshowed increased opacification of the lungs. Hy-potension and oxygen desaturation to 70% oc-curred. Dopamine, morphine, midazolam, vanco-mycin, normal saline, sodium bicarbonate, redcells, increased oxygen supplementation, and high-frequency oscillator ventilation were adminis-tered. Nitric oxide was administered, and oxygensaturation rose transiently to 86%, followed by

worsening hypoxemia, anuria, and bradycardia.The neonates mother was informed and came tothe NICU; she requested the presence of thehospital chaplain, who arrived shortly thereafter.Epinephrine was administered and positive-pres-sure ventilation and chest compressions were be-gun. However, refractory asystole developed, andthe patient died early on his seventh day of life.

An autopsy was performed.




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case records of the massachusetts general hospital


DIFFERENTIAL DIAGNOSIS

Dr. Elizabeth A. Catlin: May we review the imagingstudies?

Dr. Randheer Shailam: A radiograph from thepatients first day of life (Fig. 1A) shows that thelung volumes are normal; however, there are dif-

fuse reticular and granular opacities bilaterally,features consistent with the respiratory distresssyndrome. On the patients second day of life(Fig. 1B), there is a mild increase in the lungvolumes as compared with the previous exami-nation, but the volumes remain in the normalrange. The reticular and granular opacities thatare consistent with the respiratory distress syn-drome persist in both lungs.

On the patients third day of life, ultrasonog-raphy of the brain revealed a hyperechoic area inthe right caudothalamic groove that was consis-

tent with hemorrhage in the germinal matrix;there was a smaller germinal-matrix hemorrhagein the left caudothalamic groove. The central por-tion on the right germinal-matrix hemorrhage washypoechoic, suggesting that this is not acute. Onthe fifth day of life, a chest radiograph obtainedafter extubation showed normal lung volumes.However, there was a new hazy opacity in theright perihilar region and right upper lobe ob-scuring the right cardiac border, most likely rep-resenting atelectasis superimposed on findingsof the respiratory distress syndrome.

A chest radiograph obtained after reintubationon the fifth day of life (Fig. 1C) showed worsen-ing opacification at the right lateral base, obscur-ing the costophrenic angle, and increased right-ward cardiomediastinal shift, features consistentwith worsening atelectasis in the right lung.

A radiograph obtained on the sixth day of life(Fig. 1D) showed diffuse abnormalities involvingboth lungs and completely obscuring the rightcardiomediastinal border. In the left upper lungzone was a new opacity with air bronchograms.

The opacification in the right hemithorax hadprogressed. These findings were thought to rep-resent worsening atelectasis and edema super-imposed on the respiratory distress syndrome.Approximately 16 hours later, a chest radiographshowed progressive opacification of both hemi-thoraxes, new bilateral apical lateral opacities,and the appearance of pleural fluid.

Dr. Manuella Lahoud-Rahme: The first echocar-

diogram, obtained on the third day of life (Fig.2A, 2B, and 2C), showed normal segmental anato-my, normal biventricular systolic function (LVEF,69%), a patent foramen ovale with left-to-rightshunting, a patent ductus arteriosus (2.3 mm) withleft-to-right shunting across it, and a peak systolicgradient of 14 mm Hg suggesting pulmonary

pressures that were elevated but were 80% ofsystemic pressures. The study was normal for age,with a moderately large patent ductus arteriosusand elevated pulmonary pressures.

On the sixth day of life, a repeat echocardio-gram (Fig. 2D through 2G), obtained semiurgently,showed concentric biventricular hypertrophy, smallventricular cavities, preserved biventricular func-tion (LVEF, 61%), and no evidence of shuntingacross a patent ductus arteriosus. With the useof color Doppler imaging, the patent foramenovale was again seen with left-to-right shunting.

In addition, there was a small inferior pericardialeffusion and no evidence of tamponade.

In this patient, biventricular hypertrophy de-veloped over a period of 3 days, with preservedsystolic function. The biventricular hypertrophywas most likely due to intravascular depletion andunderfilling of both ventricles.

Dr. Catlin: I am aware of the diagnosis in thiscase. This newborn boy, born prematurely at agestational age of 29 weeks, had a relatively typi-cal course in the NICU until suddenly, on his sixthday of life, progressive multiorgan system failuredeveloped, and he died early on his seventh day oflife. For diagnostic possibilities, I considered fourcategories of neonatal disorders: inborn errors ofmetabolism, respiratory failure, cardiomyopathy,and bacterial or viral sepsis.

Inborn errors of metabolism

This patients catastrophic clinical collapse at theend of his first week of life raises the possibilityof an inborn error of metabolism. Inborn errors ofmetabolism in newborns consist of a heteroge-

neous group of disorders with similar presenta-tions.1 Pregnancy and delivery are usually un-complicated; neonates are often healthy at birth,as in this case, but metabolic imbalances maydevelop during the first week of life, in associa-tion with poor feeding, vomiting, excessive sleep-iness, and lethargy. A number of features suggesteda metabolic disorder in this patient, includingrapid and stunning clinical deterioration, lack of




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Table1.LaboratoryData.*

Variable

ReferenceRange,

Age-Adjusted

OnAdmissiontothe

NICU,3.75Hr

after

Birth

12to16Hr

afterBirth

3rdDay

ofLife

6thDayofLife

7thDayofLife

Hematocrit(%)

45.067.0

49.7(ref4

2.060.0)

46.4

42.0

37.0

Hemoglobin(g/dl)

14.522.5

16.7(ref1

3.519.5)

15.0

13.8

White-cellcount(mm

3)

940034,000

8100(ref90

0030,000)

6200

6200

15,300

Differentialcount(%,adjustedfornucle-

atedredcells)

Polymorphonuclearleukocytes

5362

51(ref

6687)

57

49

50

Bandforms

010

4

2

8

9

Lymphocytes

2134

32(ref

2237)

31

33

17

Monocytes

411

1

3

10

5

6

Eosinophils

08

0

0

0

2

Other

0

1atypicallymphocyte,

1myelocyte,

3metamyelocyes

3pro

myelocytes,9myelo-

c

ytes,4metamyelocytes

Nucleatedredcells(per100whitecells)

0

1

2

15

3

3

Plateletcount(mm

3)

150,000450,000

239,000

211,000

164,000

120,000

Peripheralsmeardescription

1+anisocyto

sis,1+poly-

chromasia,3+mac-

rocytes

1+anisocytosis,1+polychro-

masia,2+hypochromasia,

3+macrocytes,1+schisto-

cytes,1+tea

rdrops

1+anisocytosis,1+poly-

c

hromasia,2+hypochro-

m

asia,3+macrocytes,

1

+schistocytes

Sodium

(mmol/liter)

135145

138

14

1

123

Potassium(mmol/liter)

4.05.6

4.6

4.6

6.0

Chloride(mmol/liter)

98106

106

11

1

Carbondioxide(mmol/liter)

19.022.0

24.1

23

.8

Glucose(mg/dl)

60100

4

2

99

10

3

163

169

Ureanitrogen(mg/dl)

520

17

27

Calcium

(mg/dl)

8.510.5

7.4

9.8

Ionizedcalcium

(mmol/liter)

1.141.30

1.48




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response to antibiotics, cardiac hypertrophy andshock, metabolic acidosis, lethargy, and multior-gan-system dysfunction.2

The inborn errors of metabolism that presentdramatically in newborns include organic acide-mias, primary lactic acidoses, urea-cycle defects,disorders of carbohydrate metabolism, disorders

of amino acid metabolism, and fatty-acid oxida-tion defects.1 Some infants with organic acide-mias have distinctive urinary odors (e.g., the odorof maple syrup in maple syrup urine disease orthe odor of sweaty socks in isovaleric acidemia).This patient had no unusual odors, and severelactic acidosis developed only in the context ofprogressive hypoxemia and hypotension, makinga primary lactic acidosis unlikely.

Galactosemia was not considered likely, be-cause the patient did not have vomiting or patho-logic jaundice. Patients with fatty-acid oxidation

defects may present with features similar to thoseseen in this patient, including cardiomegaly andpossible pulmonary edema, but this patient did nothave other characteristic features such as seizures,encephalopathy, hypotonia, or hypoglycemia. Theresults of this patients panel of tests conductedby the Massachusetts newborn screening pro-gram showed no evidence of an inborn error ofmetabolism.3,4

Neonatal Respiratory Failure

This neonate showed signs of respiratory distressimmediately after birth. In a patient with a gesta-tional age of 29 weeks, the fetal lungs are biochem-ically and morphologically immature; approxi-mately 30% of such neonates have the respiratorydistress syndrome. In this newborn, the progres-sive respiratory insufficiency, findings on chestradiographs, and favorable response to intratra-cheal surfactant supported the diagnosis of therespiratory distress syndrome. Neonatal pneumo-nia may be radiographically indistinguishable fromthe respiratory distress syndrome, which is why

treatment with antibiotics is typically instituted.5

The patients second episode of respiratoryfailure was most likely caused by a patent ductusarteriosus in which left-to-right shunting of bloodcaused cardiomegaly, pulmonary edema, andventilationperfusion mismatch. Pharmacologicclosure of the patent ductus arteriosus correlatedwith resolution of the second episode of respira-tory insufficiency.

When a third episode of respiratory failure oc-Bloodgasanalysis

Typeofspecimen

Unspecified

Venous

Veno

us

Venous

Venous

Fractionofinspiredoxygen

Unspecified

Unspecified

0.24

0.45

0.57

pH

Unspecified7.32

7.45,venous

7.307.40

7.3

5

7.45

7.24

7.25

7.11

Partialpressureofcarbondioxide

(mmHg)

Unspecified35

50,venous3850

47

32

61

57

75

Partialpressureofoxygen(m

m

Hg)

Unspecified40

90,venous3550

61

100

30

33

19

Bicarbonate(mmol/liter)

1922

25

22

25

24

23

Baseexcess(mmol/liter)

1.0

1.3

3.4

3.9

7.1

*NICUdenotesneonatalintensivecareunit,andrefreferencerange.Toconvertthevaluesforglucosetomillimolesperliter,multiplyby0.05551.Toconvertth

evaluesforureanitro-

gentomillimolesperliter,multiplyby0.357.Toconvertthevaluesforcalcium

tomillimolesperliter,multiplyby0.2

50.Toconvertthevaluesforionizedcalcium

tomilligramsper

deciliter,divideby0.250.

Referencevaluesareaffectedbymanyvariables,includingthepatientpop

ulationandthelaboratorymethodsused.TherangesusedattheMassachusettsGen

eralHospitalareage-

adjustedandareforpatientswhodonothavemedicalconditionsthatcouldaffecttheresults.Theymaythereforenotbeappropriateforallpatients.




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curred, a consideration was that the ductus arte-riosus had reopened or that pneumonia had devel-oped. Antibiotic coverage was broadened for thepossibility of a new pneumonia. Radiographic evi-dence consistent with pulmonary edema andclinical decline prompted repeat echocardiogra-phy. The results unexpectedly showed that biven-tricular hypertrophy had developed, suggesting

that some of the clinical findings had a cardio-genic cause, such as a cardiomyopathy.

Neonatal Cardiomyopathy

Neonatal cardiomyopathies are uncommon andmay be part of systemic diseases, including ge-netic syndromes, metabolic diseases, and neuro-muscular disorders.6 On physical examination,

A B

DC

Figure 1. Radiographic Studies.

A chest radiograph obtained within 24 hours after the patients admission to this hospital (Panel A) shows bilateral

diffuse reticular and granular opacities (arrows), findings compatible with the respiratory distress syndrome. Thelung volumes are normal in this intubated patient. A radiograph obtained after the first extubation (Panel B) shows

mild reticular and granular opacities (arrows), findings compatible with the respiratory distress syndrome. The lungvolumes remain normal after extubation. A chest radiograph obtained after a third episode of respiratory failure and

reintubation (Panel C) shows multifocal patchy opacities (arrows) in the right upper, middle, and lower lung zones,features suggestive of atelectasis superimposed on the respiratory distress syndrome (arrowhead). Hazy opacities

are suggestive of pulmonary edema. A radiograph obtained during the final period of clinical deterioration (Panel D)shows bilateral patchy opacities with air bronchograms (arrowheads) and small bilateral pleural effusions (arrows).




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this neonate was entirely nondysmorphic, andhis neuromuscular examination was consistently

normal for his gestational age. The two cardiacultrasound studies showed preserved systolicfunction and no evidence of hypokinesis, poorcontractility, or an abnormal LVEF. Nonetheless,patients with severe neonatal hypertrophic car-diomyopathy caused by a novel homozygoussplice-site mutation in MYBPC3 (encoding cardiacmyosin-binding protein C), for example, typicallypresent with signs of congestive heart failureduring the first weeks of life.6 Thus, this patient

could have had an atypical presentation of anevolving cardiomyopathy.

Neonatal Sepsis

Neonates with very low birth weight (

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include temperature instability, lethargy, apnea,jaundice, respiratory distress, rashes, poor perfu-sion, irritability, and poor feeding. This patienthad several of these signs, leading to the clinicalsuspicion of severe sepsis syndrome.

Summary

In conclusion, I believed this patients illness anddeath were probably due to overwhelming bacte-rial or viral sepsis. I believed that the sepsis ledto irreversible systemic hypotension, hypoxemicrespiratory failure (due to pneumonitis and pul-monary edema), severe metabolic acidosis, andacute renal failure.

Dr. Elizabeth A . Catlins

Diagnosis

Multiorgan system failure, probably due to over-

whelming bacterial or viral infection with sepsis;a cardiomyopathy cannot be ruled out.

Pathological Discussion

Dr. Madelyn Lew: There were two major clinicalconcerns that we were asked to address at theautopsy: the cause of respiratory distress andthe possibility of a cardiomyopathy to explain thesudden cardiac decompensation.

The patient weighed 1340 g and had a crownrump length of 24.3 cm, features consistent witha newborn at a gestational age of 29 weeks. Therewere bilateral serous pleural effusions measur-ing approximately 25 ml and 20 ml in the rightand left pleural cavities, respectively. The lungswere pale, firm, and heavy, weighing 49.1 g incombination (normal weight for a gestational ageof 29 weeks, 25.312.6). Examination of the heartrevealed slight cardiomegaly (10.2 g; normalrange for a gestational age of 29 weeks, 7.22.7)and a probe-patent ductus arteriosus. The remain-der of the gross examination revealed structur-

ally normal organs with diffuse mottling.Histologic examination of the heart revealeda normal myocardium with no hypertrophy, in-flammation, or necrosis to indicate involvementby a myocarditis or cardiomyopathy. More than50% of the evaluated lung parenchyma containedmultiple hemorrhagic infarcts with adjacent airspaces filled with fibrin and inflammatory cells.The interstitium adjacent to these infarcts con-tained enlarged cells with cherry-red nuclear in-clusions, findings consistent with viral inclusions

(Fig. 3A). Multiple microscopical fields of theliver (Fig. 3B) and adrenal glands (Fig. 3C) con-tained similar patches of necrosis associatedwith cells containing nuclear inclusions. The dif-ferential diagnosis of nuclear inclusions includesmany viral causes, including cytomegalovirus,HSV, parvovirus, varicellazoster virus, and mea-

sles virus. However, the morphologic features ofthese nuclear inclusions and the pattern of organinvolvement are most consistent with infectionwith HSV type 1 (HSV-1) or type 2 (HSV-2). Im-munohistochemical analysis (Fig. 3D) showedstaining of these cells for HSV-1 and HSV-2. Theimmunohistochemical stains for HSV-1 andHSV-2 use antibodies that react to common an-tigens present in both serotypes.

Neuropathological examination revealed agerminal-matrix hemorrhage that extended intothe right lateral ventricle. There was focal in-

farction in the developing white matter underly-ing the germinal matrix. Immunohistochemicalanalysis for HSV-1 and HSV-2 was negative.There was no evidence of meningitis or en-cephalitis.

The slides and paraffin blocks of specimensobtained from the placenta were evaluated at Mas-sachusetts General Hospital. There was no evi-dence of chronic villitis, chorionic-plate thrombi,plasma-cell deciduitis, or viral inclusions to indi-cate HSV infection. Immunohistochemical analy-sis for HSV-1 and HSV-2 was negative.

In summary, the autopsy findings are diagnos-tic of systemic HSV infection involving the liver,adrenal glands, and lungs. We concluded that thepatients respiratory distress was due to viral pneu-monia and the shock was due to viral sepsis. Thebrain infarct was most likely secondary to stress,including sepsis, whereby shunted blood flow tothe heart and lungs led to ischemic changes inthe brain.

Neonatal HSV infection

Dr. H. Shaw Warren: Both HSV-1 and HSV-2 arecommon in pregnant women and can cause neo-natal infection.8-10 Neonatal HSV infection oc-curs in approximately 1 in 3200 deliveries10 andmay present with three syndromes11,12 that fre-quently overlap: involvement of skin, eyes, mouth,or a combination; neurologic infection; and dis-seminated infection. Disseminated infection, seenin this patient, is difficult to diagnose becausenonspecific signs of severe organ failure pre-dominate, as they did in this case. Diagnosis is




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often delayed, and infection with HSV is oftendiscovered only at autopsy, as in this case.

When and where did this newborn acquireHSV? In utero infection is rare (estimated at ap-proximately 1 in 100,000 deliveries)11 and isunlikely in this patient because of the uninvolvedplacenta and because such neonates usually have

signs of chronic skin, eye, and neurologic involve-ment.11 An estimated 85% of cases are acquiredat birth. Risk factors for transmission include thepresence of HSV in the birth canal, prolongedrupture of membranes, vaginal delivery, and theuse of fetal monitors.10 Both the short durationof ruptured membranes and the cesarean sec-tion would have reduced the risk of transmissionfrom the mother in this case. The highest risk tothe neonate (risk of transmission, 30 to 50%) isprimary maternal infection close to delivery,10,13,14

leading to a high quantity of virus and an ab-sence of type-specific HSV antibody passed to theneonate. The risk of transmission from motherswho have recurrent infection at the time of de-livery is much lower (risk of transmission,

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HSV-2 very slightly elevated. Many laboratoriesuse assays that cross-react between HSV-1 andHSV-2, mixed-antigen preparations, or both, aswas done here. Furthermore, titers of IgM anti-bodies to HSV can increase with recurrent epi-sodes of HSV infection, so that an elevated IgMtiter does not necessarily prove primary infec-

tion.16-18 Although the antibody levels are con-sistent with the possibility that the mother hada primary infection with one type and an oldinfection with the other type, the results are notdefinitive. Postnatal acquisition of HSV throughexposure to a caregiver is estimated to causeabout 10% of cases of neonatal HSV.11 On bal-ance, it seems most likely that the patient ac-quired the infection from the mother at the timeof birth.

Even poring over this case retrospectively, therewere no clear clues to the diagnosis that might

have prompted antiviral treatment with acyclovir.Many infections can cause severe sepsis in a6-day-old neonate, including infection withmany strains of bacteria and with viruses suchas adenovirus and enterovirus, in addition toHSV. Sepsis is common in this population, andoccult disseminated HSV is rare; therefore, em-pirical treatment with acyclovir of all neonateswith sepsis syndrome is not warranted.

Dr. Nancy Lee Harris (Pathology): Dr. Ecker,would you comment on strategies for preventionof maternalfetal HSV infection?

Dr. Jeffery L. Ecker (MaternalFetal Medicine):Women with a history of HSV infection are oftenprescribed acyclovir in the last weeks of preg-nancy to reduce the risk of recurrence and therisk of neonatal HSV infection at the time ofdelivery. Regardless of such prophylaxis, obste-tricians will plan cesarean delivery in cases ofgenital lesions or symptoms suggestive of recur-rent HSV at the time of labor, of rupture ofmembranes, or of an otherwise indicated orplanned delivery. Delivery during a primary HSV

infection is associated with a high risk of neo-natal HSV infection, but reducing transmissionmay be challenging, especially if there are nosymptoms or lesions that are suspicious forgenital HSV. Some researchers and clinicianshave suggested that discordant couples inwhich the woman has no serologic evidence ofpast HSV infection and her partner does havesuch evidence may be encouraged to make

behavioral changes (e.g., the use of barrier meth-ods) to prevent primary maternal HSV infectionduring pregnancy. Such strategies remain a mat-ter of debate, discussion, and study.

Dr. Catlin: This newborns death was devastat-ing to his mother. Parents never completely re-cover from the death of a child19; for many par-

ents, it is the single most traumatic event in theirlives. The NICU health care providers also grieve,struggle to make sense of the situation,20,21 andexperience stress when a newborn patient dies.22I was in close contact with the patients motherwhile we awaited postmortem results. Once thediagnosis of systemic herpes infection, withoutplacental involvement, was made, concern wasraised about acquisition of herpes by the new-born in the hospital. We have a policy in all thenurseries that staff members with herpetic le-sions cannot work until cleared by Occupational

Health services. Nonetheless, Margaret D. Settle,R.N., Ph.D., NICU Nurse Director, systematicallyreviewed staffing assignments for this patient, andeach caregiver was interviewed regarding herpeticlesions. We similarly questioned the physicians.No herpetic lesions were discovered. Thus, we wererelatively confident that the herpes infection wasnot acquired in this hospital.

I reported the results of the postmortem ex-amination to the mother and suggested that shebe checked for HSV infection. She went to theclinic, asking to be checked for herpes. Sero-logic samples were drawn, but a physical exami-nation was not performed, so we do not knowwhether she had a current lesion. She now seemsto be doing well emotionally.

Dr. Harris: What is the status of a possible HSVvaccine?

Dr. Warren: To date, attempts to develop sucha vaccine have not been successful.

ANATOMICAL DI AGNOSIS

Neonatal herpes simplex virus infection, involvingthe lungs, liver, and adrenal glands, with sepsis.This case was presented at the Pediatric Grand Rounds.Dr. Catlin reports receiving consulting fees from Medical Pro-

fessional Mutual Insurance. No other potential conflict of inter-est relevant to this article was reported.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.

We thank Dr. Drucilla Roberts for supervising the postmor-

tem examination and assisting in the preparation of the patho-logical discussion and images.




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Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences

Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or referencematerial is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of theimages from the CPC, not only those published in theJournal. Radiographic, neurologic, and cardiac studies, gross specimens,and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of theCase Record.

The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current

subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail [email protected].

REFERENCES

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3. Perrin JM, Knapp AA, Browning MF,et al. An evidence development processfor newborn screening. Genet Med 2010;12:131-4.4. Levy PA. An overview of newbornscreening. J Dev Behav Pediatr 2010;31:622-31.5. Shani L, Weitzman D, Melamed R,Zmora E, Marks K. Risk factors for earlysepsis in very low birth weight neonateswith respiratory distress syndrome. ActaPaediatr 2008;97:12-5.6. Xin B, Puffenberger E, Tumbush J,Bockoven JR, Wang H. Homozygosity fora novel splice site mutation in the cardiacmyosin-binding protein C gene causes se-

vere neonatal hypertrophic cardiomyopa-thy. Am J Med Genet A 2007;143A:2662-7.7. Fanaroff AA, Stoll BJ, Wright LL, et al.Trends in neonatal morbidity and mortal-ity for very low birthweight infants. Am JObstet Gynecol 2007;196(2):147.e1-147.e8.8. Xu F, Markowitz LE, Gottl ieb SL, Ber-man SM. Seroprevalence of herpes sim-

plex virus types 1 and 2 in pregnant wom-en in the United States. Am J ObstetGynecol 2007;196(1):43.e1-43.e6.9. Roberts CM, Pfister JR, Spear SJ. In-creasing proportion of herpes simplex vi-rus type 1 as a cause of genital herpesinfection in college students. Sex TransmDis 2003;30:797-800.

10. Brown ZA, Wald A, Morrow RA, SelkeS, Zeh J, Corey L. Effect of serologic statusand cesarean delivery on transmissionrates of herpes simplex virus from motherto infant. JAMA 2003;289:203-9.11. Kimberlin DW. Neonatal herpes sim-plex infection. Clin Microbiol Rev 2004;17:1-13.12. Corey L, Wald A. Maternal and neona-tal herpes simplex virus infections.N Engl J Med 2009;361:1376-85. [Erra-tum, N Engl J Med 2009;361:2681.]13. Brown ZA, Benedetti J, Ashley R, et al.Neonatal herpes simplex virus infectionin relation to asymptomatic maternal in-fection at the t ime of labor. N Engl J Med

1991;324:1247-52.14. Brown ZA, Selke S, Zeh J, et al. Theacquisition of herpes simplex virus dur-ing pregnancy. N Engl J Med 1997;337:509-15.15. Baldwin S, Whitley RJ. Intrauterineherpes simplex virus infection. Teratology1989;39:1-10.

16. Morrow RA, Brown ZA. Common useof inaccurate antibody assays to identifyinfection status with herpes simplex virustype 2. Am J Obstet Gynecol 2005;193:361-2.17. Gardella C, Brown ZA. Managinggenital herpes infections in pregnancy.Cleve Clin J Med 2007;74:217-24.

18. Page J, Taylor J, Tideman RL, et al. IsHSV serology useful for the managementof first episode genital herpes? SexTransm Infect 2003;79:276-9.19. Reilly-Smorawski B, Armstrong AV,Catlin EA. Bereavement support for cou-ples following death of a baby: programdevelopment and 14-year exit analysis.Death Stud 2002;26:21-37.20. Cadge W, Catlin EA. Making sense ofsuffering and death. How health care pro-viders construct meaning in a neonatalintensive care unit. J Relig Health 2006;45:1-15.21. Catlin EA, Guillemin JH, Thiel MM,Hammond S, Wang ML, ODonnell J.

Spiritual and religious components of pa-tient care in the neonatal intensive careunit: sacred themes in a secular setting.J Perinatol 2001;21:426-30.22. Stern TA, Jellinek MS. Training issuesin the intensive care unit. New Horiz1998;6:398-425.Copyright 2012 Massachusetts Medical Society.


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