- Email: [email protected]
Rickettsial vasculitis
ickettsial
William
vasculiti
Walker, M.D.* D. Mattern, M.D.**
Chapel Hill, 7% C.
Important rickettsial diseases of man are distributed over all the continents with the exception of Antarctica. In order to approach these diseases, their etiologic agents must be defined taxonomitally. Definition of the term rickettsia varies from a nearly meaningless inclusiveness of almost any intracellular microorganism to a narrower consideration of only the genus Rickettsia. In this discussion, the other related genera Coxiella ( fever) and Rochalimaea (trench fever), will be excluded. Members of genus Rickettsia share the following characteristics: gram negative bacterial ultrastructural morphology, obligate intracellular parasitism, ecologic niche including all or a portion of life spent in an arthropod host, and serologic grouping relationships. There are three serologic groups: typhus group, spotted fever group, and scrub typhus group. The concept that rickettsiae are an intermediate form of life between viruses and bacteria is completely outmoded. That they are clearly a specialized group of bacteria is confirmed by method of replication (binary fission), content of both RNA and DNA, ultrastructural morphology, and sensitivity to antimicrobial agents.’ Although rickettsiae are capable of penetrating and growing witbin a wide variety of host cells of various species and organ sources, in man they are found only in vascular endothelium and, in some diseases, vascular smooth muscle. This anatomic distribution determines the basically similar pathology (vasculitis) From North Received
the Departments Carolina School for publication
of Pathology and Medicine, University of Medicine, Chapel Hill, N. C. Nov.
14, 1979.
Reprint of North
requests: Carolina,
Dr. David H. Walker, School of Medicine,
Dept. of Pathology, University Chapel Hill, N. C. 27514.
*Dept. cine.
of Pathology,
University
of North
Carolina
School
of Medi-
**Dept. cine.
of Medicine,
University
of North
Carolina
School
of Medi-
896
December,
1980, Vol. 100, No. 6, part
1
of
and pathophysiology (increased vascular ability) of the rickettsial diseases. Geographic distribution of rickettsial diseases reflects the distribution of infected arthropod hosts and their contact with man. Rickettsial diseases of man, their etiologic agents, vectors, and geographic distribution are resented in Table I. Although other rickettsiae have been discovered in various econiches in the United States, at this time only Rickettsia rickettsii (Rocky Mountain spotted fever), Rickettsia mooseri (murine typhus), Rickettsia prowazeki (recrudescent typhus), and Rickettsia czkari (rickettsialpox) have been documented as etiologic agents of disease in man in recent times. Evidence indicates that epidemic typhus has probably been transmitted to man from a natural zoonotic cycle of Rickettsia prowazeki in flying squirrels in the southeastern states? and that Rickettsia canada possibly causes a diseasesimilar to Rocky Mountain spotted fever.” Mowever, in current reports Rocky Mountain spotted fever (RMSF) accounts for more than 90% of rickettsial disease,with murine typhus a distant second in incidence and the others apparently quite rare.’ The incidence of RMSF has risen to a kigh level with continued significant mortality. In 1959 only 199 caseswere reported, and by 1968 the annual total was still only 298 cases. Since that time a remarkable increase has occurred, peaking at a total of 1,153 cases in 1977.5 Expressed as rates this is a rise from 0.11 cases per 100,000 population in 1959 to 0.50 cases per 100,000 nationally and 1.66 cases per 100,000 in the South Atlantic states in 1977. Although the mortality rate has fallen from 20% in the preantibiotic era, it has remained in the 5 to 10%range to the present time despite the efficacy of tetracycline and chlorampbenicol. RMSF has been reported from 46 0002-8703/80/120896
+ 11$01.10/O
0 1980
The
6. V. Mosby
Co.
Rickettsial
Table
vasculitis
I Disease
/Etiology
Typhus group Epidemic typhus
Vector
Geographic
distribution
R. prowazeki
Louse
R. prowazeki
Ectoparasite of flying squirrels None
Murine typhus Spotted Fever group Rocky Mountain spotted fever Old-world tick-borne spotted fever (Bou-. tonneuse fever, South African tick.. bite fever, Kenya typhus, etc.) Siberian tick typhus Queensland tick typhus Rickettsialpox
R. mooseri
Rat
R. rickettsii
Tick
R. conori
Tick
U. S., especially southeastern Brazil, Colombia, Mexico, Mediterranean basin, Africa,
R. sibirica R. australia
Tick Tick
Siberia Australia
R. akari
Mite
Central European tick typhus Scrub Typhus group Scrub typhus
R. slovaca
Tick
Probably worldwide; documented U. S. S. R. Central Europe, Armenia
R. tsutsugamushi
Mite
Eastern
Recrudescent
typhus
flea
states; however, there is a higher incidence in the southeastern states with North Carolina, Virginia, Tennessee, Oklahoma, South Carolina, Georgia, and Maryland reporting 66.1% of all cases between 1975 and 1977.5Casesoccur most often in children, in males, and between mid-April and mid-September. Moreover, mortality rates are higher for adults (over age 30, 13.9% vs. 5.4% under age 30), males (8.2% vs. 4.5% in females), and nonwhites (13.9% vs. 5.8% in whites): Fatal cases seek medical attention at the same time during the course of illness as nonfatal cases. However, their rash appears later; they give a history of tick bite less often or later in the course; and initial or unexpected symptoms lead to misdiagnosis. As a result of incorrect or delayed diagnosis, antirickettsial treatment is not given or is given too late to be effective.7 Effect
of rickettsiae
on the
microcirculation.
Dermal involvement in rickettsial diseasesis not only a prominent clinical sign but also an opportunity to observe and evaluate the nature of the American
Heart
Journal
Historic: all continents except Australia Recent: Burundi, Rwanda, Uganda, Ethiopia, Algeria, Chad, Niger, Zambia, Nigeria, Zaire, Liberia Bolivia, Peru, Ecuador, Chile, Guatemala, Costa Rica, Mexico Southeastern U. S.
Worldwide, especially localities of previous typhus demics, eg., Poland and Yugoslavia; or countries migration of previous typhus cases, eg., U. S. and Canada Worldwide, especially in warmer climates including
and southern
Asia
states; Panama Asia
western
in cities
and southwestern
epiof im-
U. S.
Canada,
of U. S. and
Pacific
vascular events. The observations indicate that the microcirculation is the primary target, with variable subsequent contiguous centripetal extension to arteries and veins. The temporal sequence of events which may be seen in the skin of patients with typhus and RMSF reflects the pathologic and pathophysiologic events in these diseases. The rash of RMSF is delayed, usually occurring three days after onset of fever with a range of 2 to 7 days and rarely not appearing at all.*-” The rash tends to appear first on ankles, feet, wrists, and hands, and to spread centripetally to involve the entire body within 24 to 36 hours, usually including the palms and soles. This centripetal spread contrasts with the centrifugal spread of the rash of typhus. The difference has never been satisfactorily explained, although optimal growth of Rickettsia rickettsii at lower temperaturesI would favor earlier attainment of a critical mass of pathogenic organisms in peripheral sites. Initially, the rash consists of pink, unelevated 897
Walker
and
Mattern
macules which are from less than one to five millimeters in diameter, blanch co temporarily on pressure, and are Subsequently these lesions acquire a deep to-purple hue and increase in size, e confluent in some cases. onset, the rash becomes chial. In severe cases during the third week necrosis of dependent peripheral parts, including scrotum, prepuce, fingers, toes, and external ear may occur. Study of the pathologic lesions in rickettsial disease has been performed most comprehensively in epidemic louse-borne typhus. Wolbach, who already had extensive experience in investigating RMSF, was sent to Poland with the Typhus Research Commission during World War I[. descriptions based on the stu y of skin from 36 necropsies and skin biopsies from 28 patients covered the range from the first day of rash to the twenty-fourth day of disease.l” At the onset sf rash (day 3 of disease), the only pathologic lesion was “swelling of the endothehum of capillaries and small arteries and veins” of the papillary an reticular dermis. Rickettsiae were observed in swollen endothelial cells. On day 5 of the disease, arterioles an venules demonstrated mural ng swollen endothehal cells which frequently contained numerous rickettsiae. vascular reaction was minimal. Subsequently contiguous spread of rickettsiae with accumulation of increased quantity of organisms was observed in serial sections; moreover, the pathologic lesions involved larger vessels in the deep dermis and subcutaneous tissue nt perivascular memo ermal hemorrhages were ob aries and vessels of size” on and after the eighth day of illness. Organization of vascular tbrombi was seen as early as the fifteenth day. Areas of gangrene were demonstrated microscopically not to be aceo panied by thrombosis of large vessels but to due to thrombosis of capillaries and small arternes and veins beginning in the dermis and extending centripetally. Comparison of the lesions of typhus and RMSF is most remarkable for their similarity. owever, differences which comprise more extensive destruction of the vascular wall including the media and less pronounced perivascular inflammation in RMSF reflect infection of vascular smooth
muscle by Rickettsia rickettsii and not ~~~~et~~~~ prowazeki and the generally shorter course of fatal casesof RMSF. “Rarely in any disease are the pathologic Iesions correlated so closely with the clinical picture . . f A careful study of the patient’s clinical record will reveal a very close correlation between the microscopic findings and the physiologic disturbances, although the latter may be out of all proportion to the visible anatomic lesions.‘912 These comments by Hare11in his review of in 1949 certainly apply to the physiologic bances in the peripheral circulation in the nmre severe rickettsial infections such as epidemic typhus, scrub typhus, and RMSF. Hn 1944 reP1,referring to RMSF,‘” and Woodward ring to epidemic typhusYxGpostulated in separate publications that hypotension and circulatory collapse seen at &e height of these rickettsial infections resulted not from “cardiac weakness,” but from peripheral circulatory failure, the latter resulting from a decrease in blood volume as a consequence of an increase in systemic capillary permeability. They both noted that the falhng blood pressure at the height of the illness coincided with the appearance of edema and with a concentration of serum proteins, particn a more detailed investigation of the pathophysiology of the peripheral circulatory failure 9n RMSF, Harrell in 1949 reported serial observations in 13 patients.‘? The entire natural bistory of the illness was observed, since neither tetracycline nor chloramphenicol was, then available as specific treatment. Sequential measurements of plasma volume (using Evans Blue dye), “extravascular volume” (using thiocyanate space), and the serum concentrations of total protein, albumm, nonprotein nitrogen (NPN), an were correlated with various chnica tions, and the effect of intravenous therapy with crystalloid-and colloid-containing solutions was noted. The illness was considered mild if the tourniquet test was negative, there was no e and the pulse and blood pressure were stable; moderate if the tourniquet test was positive, the was slight edema, the pulse rate was increas and the patient appeared toxic; an severe if there were purpura, marked edema, and delirium. Cases with a fulminant clinical course were not included. Data were summarized for the moderate to severe cases at three stages: (I) soon after
December,
1980, Vd. 100, No. 6, part
1
Rickettsial
onset of the rash, (2) at the height of illness 9 to 14 days after onset of the rash, and (3) during the recovery period in the third week after onset of the rash. Patients presented shortly after the appearance of the rash with clinical signs of dehydration, an elevated NPN and low serum chloride concentration, a normal or slightly low serum protein concentration and plasma volume, a normal thiocyanate space, and a low normal blood pressure. When intravenous therapy with crystalloid solutions was given in an effort to correct the dehydration at this point in the illness, there was a prompt fall in the NPN and a rise in serum chloride concentration. Plasma volume rose transiently, and there ‘was a reciprocal fall in the serum protein concentration. If crystalloid solutions were continued, the expansion of plasma volume was sustained and there was a striking rise in the thiocyanate space, coinciding with the development of progressive peripheral edema. At the height of the illness, the onset of hypotension was associated with a more marked reduction in the serum protein concentration and plasma volume, elevated thiocyanate space, and peripheral edema. Crystalloid administration at this point accelerated the extravascular accumulation of fluid with’out a favorable effect on the blood pressure or plasma volume. The onset of recovery was marked by return of temperature to normal and a reversal of the above abnormalities. The blood pressure rose to normal as plasma volume began to increase. The thiocyanate space gradually decreased as edema was mobilized and diuresed; and finally, the serum protein concentration returned to normal. The administration of colloid solutions, such as plasma or albumin, in contrast to crystalloids, did support the blood pressure and plasma volume at the height of illness and early in the recovery period, but in five of the six instances reported its administration also precipitated acute pulmonary edema. These findings were interpreted to indicate that the vasculitis of RMSF led to a progressive increase in systemic capillary permeability such that there was a gradual loss of protein from the vascular compartment and a decrease in intravascular oncotic pressure. Although this study served to characterize the sequential changes in systemic capillary permeability in the more severe cases, it left unanswered important questions about fluid therapy, and also raised
American
Heart
Journal
vasculitis
basic questions about cardiac function pulmonary capillary function in RMSF.
and
Renal pathology in rickettsial diseases. The path.ologic lesions of kidneys in rickettsial diseasesmay be considered to be either of two types: lesions due to local effects of rickettsiae on renal vessels or lesions due to the effects of systemic hypovolemic shock. In studies of typhus fever, Wolbach described focal lesions in which “only small blood vessels are affected and. . . the cellular response is infiltrative.“‘” These lesions contained capillaries or precapillary blood vessels surrounded by mononuclear phagocytes, lymphocytes, plasma cells, and polymorphonuclear leukocytes and incorporated one or several tubules in various stages of injury up to actual necrosis. Wolbach noted that these lesions were present also in scrub typhus and Rocky Mountain spotted fever, but that in all three diseases the distribution was spotty and little renal parenchyma was involved.18 In the classic description of the pathology of RMSF, Lillie observed that 12 of 17 caseshad focal lesions with “irregular interstitial and perivascular infiltration by lymphocytes, in later cases offten plasma cells and large lymphoid cells as we11.“19These lesions were especially marked at the corticomedullary junction. Focal pericapillary and interstitial hemorrhages were identified in six cases. Our study confirmed these observations and demonstrated by specific immunofluorescence that the distribution of the majority of the Rickettsia rickettsii was identical with that of the multifocal perivascular interstitial nephritis, concentrated near the corticomedullary junction.20 Another potential local effect of rickettsial infection on the kidney is thrombosis. Wolbach described precisely this relationship in typhus fever with thrombosis of vessels in the focal interstitial lesions, no lesions of large blood vessels, and one case with small mural thrombi in small arteries of the pelvic submucosa with rickettsiae in the endothelium of the affected vessels.14Our original study of ten cases of RMSF with histochemical staining for fibrin revealed thrombi only in vessels of a minority of the focal interstitial lesions and no glomerular thrombi.20 Subsequently we have investigated a case of fuLminant RMSF (defined by ParkerZ1 as fatal within 3 to 5 days of onset) which showed fibrin thrombi in approximately half of the glomeruli. Glomerular fibrin thrombi were also demon-
899
strated in the only case of f~lmin~~t RMSF with description of pathology reported in the literature2* Pn our case, study of serial sections stained for fibrin histochemically and for ettsik imm~~oh~tochemica~~y demonstrated that thrombotic glomeruli were intensely infected and that ~onthrombotic glomeruh were mi~~rna~ly or mildly infected. In an intermediate position, several recent cases with death occurring on day 6 or 7 of disease have had rare focal gl~merular tbrombi. hese observations on throm tissue from rickettsial diseases indicate that thrombosis is the response to local injury to blood vessels by rickettsiae. Two lesions which could be due to local an systemic effect of rickettsial infections are merulonephritis and edema of tb is no consensus that glomerulon occurs in rickettsial diseases. Gl was described by Allen and Spit9 in scru hus and RMSF. Ultrastru renal biopsies from five razilian cases of RMSF with various degrees of acute renal funcment demonstrated no g~orner~~o~eonly nonspecific endothelial swelling cells.*” Our cases, controlled tbickment membranes revealed no ~~orneruione~h~t~s~ a5 judged by the absence of glomerular hype~cei~~~a~ty and b ment membrane lesions. Another recent st has shown no glomerular immune complexe ~mnnofluore5cence and no ltrastructural deposits. On the other han increased renal weights, presumably secondary to edema, have ported in some cases of scrub typhus*” and 20 This edema may result from multifocal vasculitis and/or acute tubular necrosis. significant pathologic sion which is the of systemic shock on t kidneys is acute tubular necrosis (ATN). In two of 37 cases of typhus fever, heavy kidneys with pa cortices were compatible Although ATN is not alway logically in all of its time-course and autolysis often renders tubular epithehum impossible to evaluate microscopically, the stage sf ATN idenkedly thin tubular epithelium and ma has been observed in cases of hysiology
in ?~c~e~~s~a~ diseases.
With reference to clinical abnormalities of renal
function, the remote effects of the systemic vascuhtis far outweigh the effects of the observed intrarenal pathology and can best be understood as the sequential manifestations of altered systemic capillary permeability.‘0 Interestingly, the basic renal lesion, a focal, perivascular interstitial nephritis, finds little clinical expression. Early in the course of the more severe rickettsial infections, patients often present with dehydration, a moderately elevated BUN and serum creatinine concentration, mild hyponatremia teinemia, a low-normal blood pressu gressive hypovolemia. The BUN is relation to the serum creatinine ~o~ce~trat~o and the urine volume is reduced, though usual not to oliguric levels. There is a trace to i c proteinuria by reagent stick, and 24hour collections contain less than 500 mg. of protein. The urine sediment contain5 a few coarsely granular casts, but no increase in cellular elements The urine specific gravity is usually greater than 1.020 and urine sodium concentration is low, often less than 10 mEq./L. Expansion of intravascular volume with colloid or crystalloid solutions restores renal function to normal within a few days. This entire picture is consistent with prerenal azotemia. At the height of illness, in severe cases wit otracted course, acute hypotension te oliguric acute renal failure (A Despite prompt restoration of blood pressu normal and maintenance of intravasular volume, the oliguria persists. The urine c sediment are typical of ATN. ATN, in this setting, has been reported in boutonneuse fever, a milder, but related rickettsial infectionz7 but not to date in Rocky Mountain spotted fever, although the potential for recovery has been demonstrated. Oliguric acute renal failure is a regular occurrence in fulminant cases, in association with systemic circulatory collapse. Causes other than hypotension have been considered in the pathogenesis of ATN in Rocky Mountain spotted fever, specifically non~tra~matic rhabdomyolysis with myoglobinuria, but evidence to support their occurrence is lacking. As noted, histologic lesions of acute diffuse glomerulonephritis were described in one early report of RMSF. A review of published casesand our own material, however, does not reveal other documentation of this lesion, and there is no clinical data (heavy proteinuria, hematuria with
December,
1980, Vol. IN?, No. 6, part
2
Rickettsial
red cell casts) to support the occurrence of acute glomerulonephritis. Thus, the major clinical abnosrmalities in renal function, prerenal azotemia and ATN, are the early or later consequences of tbe systemic vasculitis. Recovery of renal function with prerenal azotemia is the rule, and the potential for recovery from ATN with resolution of the vasculitis is suggested. Cardiovascular and pulmonary pathology rickettsial diseases. In general, the heart
in
in typhus fever, RMSF, and scrub typhus manifests negligible gross alterations and. virtually universal microscopic interstitial mononuclear myocarditis. Wolbach felt that inflammatory infiltration of the myocardium was diffuse because of its relationship to the most diffusely distributed blood vessels, the capillaries; that the order of severity of inflammatory infiltration was scrub typhus, typhus, and RMSF; and that not much evidence of degeneration of heart muscle could be demonstrated.‘s Myocarditis was noted in a series of eight autopsies of cases of RMSF by Wilson and Chowning in 1904.‘” They noted a few epicardial petechiae, dark, fluid blood filling the right ventricle, empty left ventricle, and “considerable round cell infiltration.” Following a number of case reports by a series of authors often citing myocarditis, Lillie published the classic description of myocarditis in RMSF in his series of I7 cases.lgGrossly, he noted that “the right ventricle was more often dilated than the left, but in the majority the status of the chambers was ‘normal’ or contracted” and that “altogether gross changes were slight.” Microscopically, two cases were normal; 15 manifested “interstitial infiltration of variable density, chiefly by lymphocytes, often with lesser numbers of plasma cells, monocytes . . _a few neutrophil or eosinophil leukocytes or mast cells.” Myocarditis was “irregular and patchy. . . often distinctly centered about small vessels and in interfascicular connective tissue.” Only two cases had focal coagulative necrosis of myocardial cells. In the definitive study of the pathology of typhus, Wolbach stated that “as a rule the left ventricle was contracted and the right moderately dilated.“‘* In six postmortem examinations performed soon after death in cases without significant bacterial complications, myocardium showed pallor, loss of consistency, and yellowish streaks and points. Acute valvular lesions and
American
Heart
Journal
uasculitis
macroscopic mural thrombi were not detected. Microscopic lesions, which were observed in all 37 necropsies, included slight degrees of edema, focal and diffuse myocarditis with interstitial macrophages, lymphocytes, plasma cells, few polymorphonuclear leukocytes, and vascular lesions “almost wholly restricted to capillaries and vesselsof pre-capillary size.” Large blood vessels in the heart and pericardium very rarely contained lesions. Pathologic studies of the heart in scrub typhus have yielded essentially the same observations as in typhus fever and RMSF.‘“, 29 Besides myocarditis, there have been few consistent pathologic alterations of the heart in the rickettsial diseases. When present they have included few subendocardial mononuclear inflammatory foci, pericardial fluid varying from none to moderate to rarely large amounts, and an occasionally demonstrated focal inflammatory lesion involving a conduction bundle3” or the Purkinje conduction system. The relationship of rickettsiae to the myocarditis has been unclear. Much of this unsatisfactory state has been a result of the unreliability of the various Giemsa techniques to demonstrate rickettsiae. Even in the hands of Wolbach, who used the method to demonstrate rickettsiae successfully in many lesions of typhus and spotted fever, rickettsiae could not be satisfactorily demonstrated in heart lesions of typhus fever.14 Of 40 cases of RMSF in which Giemsa stain was reported to have been used to search for rickettsiae in heart, only a single case was reported to contain rickettsiae “within the cytoplasm of the endothelial cells of the subepicardial and interstitial capillaries.““’ In contrast, Rickettsia rickettsii were demonstrated in hearts of all eight untreated or inadequately treated casesof RMSF which were examined by a technique of deparaffinization, trypsin digestion, and specific direct immunofluorescence in our laboratory.32 Rickettsia rickettsii were observed in capillaries, venules, arterioles, and large vessels including coronary arteries in descending order of invlolvement. Vascular infection with resultant vascular injury and increased permeability provides the probable pathogenetic mechanism for moderate myocardial edema. Data on the same series of hearts with etiologically confirmed RMSF which suggested myocardial edema were increased heart weight in eight of nine casesand detectably increased interstitial volume in six of
901
nine cases.3z Absence of left ventricular dilatation indicated that severe myocardial failure was not the etiology of hypotension, shock, and death in Pathologic studies of lung in rickettsial disease have demonstrated interstitial pneumonitis with alveolar walls containing mononuclear ieukocytic infiltration.‘*~ lR. lg. z3.26.2e.33 In cases which were heated by broncbo~~eumo~ia, interstionitis was manifested grossly by congestion and edema. Further microscopic evi for loss of vascular integrity are multiple foci of alveolar hemorrhage, fibrin, and edema. Examination of lungs from cases of immunofluorescence has revealed moderate-tosevere infection of the pulmonary microcirculation by ~~~kett~i~ rick&&ii (see illustrative Case 2 below), thus providing a pathogenetic expdanation for the interstitial pneumonitis and the increased pulmonary vascula
referred to convincingly exclude any significant contribution by the heart to the development of hypotension and peripheral circulatory collapse in the course of severe rickettsial infection; but the role of the heart in the development of pulmonary edema, a less common complication, has been more difficult to elar “typhus beart,” et that “central circu and pulmonary edema were distinctly uncommon.‘” None of the 30 severely or critically ill patients he studied during the course of their illness had cardiac erdargement y physical examination, a gallop rhyth istended neck veins, or an enlarged liver. e recorded serial measurement of venous pressure. Values above 12 cm. water were not seen, and the average value was 8 cm. water. Radiographs were available in 12 patients and showed neitber eardiomegaly nor conjestion. electrocardiograms no striking deviations from normal. Rales were heard frequently, but usually in association with coarse rhonchi, and were considered to be ma~~festati~~s of tracheobronchitis or patchy bron~bo~~e~mon~a~ both of which were often observed at neeropsy. Pulmonary edema has occasionally been noted in scrub typhus, but not in conjunction with other findings of heart failure. Th critically ill or preterminal, and t
edema was considered to be a manifestation of severe rickettsial pneumonitis.‘“~ 29 Pulmonary edema has been most ~~e~~e~t~y reported in RMSF, and its pathogenesis is of criticaE importance with regard to fluid management. A careful review of the case reports of the 13 patients HarrelS. originally described in his study of peripheral circulatory failure reveals that five developed pulmonary edema during the course of their illness.17 The episodes of pulmonary edema all occurred in the second week of the illness, at the height of the changes in systemic capillary permeability, or a few days into the recovery period. The administration of solutions containing eolloid immediately preceded the development of pulmonary edema in each instance, and an increase in plasma volume was documented by the Evans method. Distended neck veins were not however, and the one recording of venous pressure during of pulmonary edema revealed a value 20. A gallop rhythm was noted in only one instance. Treatment consisted of digitalis administration and fluid restriction. There was clinical resolution of the pulmonary edema within 48 hours in four of the patients, patient developed bacterial pneumonia and died. A recent clinical study of the pulmonary manifestations in RMSF confirms and extends these observations.3’ The records of all patients at one hospital documented to have RMSF between 1973 and 1976 were reviewed. Nine of the 33 patients had deterioration in pulmonary function during the first week of hospitalization, with a widening of the alveolar-arterial oxygen difference. Seven developed radiographic infiltrates, and six developed pulmonary edema. All nine were in markedly positive fluid balance, and four had received large amounts of Auid following hypotensive episodes. None of the patients had third heart sounds, cardiac enlargement ra graphically, or electrocardiographic changes. One of the patients with severe diseasedied withm 24 hours of hospitalization. Diuresis in the other eight patients led to prompt improvement of gas exchange. Radiographic and clinical signs of pulmonary edema cleared within 48 hours. Sinee 1976 we have seen two additional cases, one which illustrates the clinical presentation of pulmonary involvement in RMSF and the other which highlights the pathological changes
Rickettsial
1. Chest radiographs in Case 1 of RMSF. On the day of admission pattern are normal. After two days of parenteral fluid administration radiologic pattern of pulmonary edema is present Fig.
Illustrative
cases
Case 1. A 48-year-old white housewife from Smithfield, N. 6. removed a tick from her scalp ten days before admission. Three days later she developed severe headache, nausea, and fever. Thereafter she had daily fevers of 40°C. and intermittent vomiting. Three days before admission a red macular rash was noted on the trunk and extremities, including the palms and soles. She was admitted to North Carolina Memorial Hospital on September 8,1978. Physical examination showed a blood pressure of 140180 mm. Hg and a temperature of 40°C. Pulse rate was 100 beats per minutes. She was oriented and alert, but appeared weak an.d acutely ill. A generalized maculopapular rash with petechial areas was noted on the trunk and extremities. The lungs were clear, the neck veins were not distended, and examination of the heart showed no enlargement or gallop rhythm. There was no peripheral edema, no adenopathy, and the neurological examination was normal. Blood chemistries included sodium 133 mEq./L., BUN 15 mg./dl., creatinine 0.8 mg./dl., calcium 8.6 mg./dl., total protein 6.5 g./dl., and albumin 3.5 g./dl. The hematocrit was 32% and the platelet count 92,OOO/pl. The prothrombin time and. partial thromboplastin times were normal. The initial chest radiograph (Fig. 1) was interpreteld as normal. A skin biopsy on the day of admission examined by specific direct immunofluorescence was diagnostic for Rocky rickettsii Mountain spotted fever with Rickettsia in dermal blood vessels.““, 36 She was begun on treatment with intravenous chloramphenicol, 100 mg. every 8 hours, and
American
Heart
Journal
(leffj, heart (right),
vasculitis
size and pulmonary vascular heart size is unchanged, but
intravenous hydration with 5% dextrose in normal saline at a rate of 75 ml./hr. On the second day after admission she developed progressive shortness of breath over a period of several hours. Examination revealed diffuse rdles, but the neck veins were not distended and no gallop rhythm was heard. The blood pressure was 160/80 mm. Hg. Arterial blood gases revealed pH 7.52, PCO, 22 torr, and PO, 30 torr. Repeat serum total protein was 6.5 g./dl. with albumin 3.0 g./dl. The electrocardiogram showed sinus tachycardia and nonspecific ST segment changes. A repeat chest radiograph was interpreted as showing pulmonary edema (Fig. 1). She was transferred to the intensive care unit where she was treated with oxygen, furosemide, and digoxin. Within three days pulmonary gas exchange had improved, and the rales and pulmonary infiltrate on chest radiograph had cleared. Her recovery was uneventful. Comment. Fluid administration in this otherwise stable patient led to the abrupt development of pulmonary edema in the absence of signs of heart failure or elevated systemic venous pressure. The predominance of infiltrates in the upper lobes is similar to that seen when pulmonary capillary wedge pressure is elevated-i.e., in cardiogenic pulmonary edema-but might have occurred at only slightly increased pulmonary capillary wedge pressure in the presence of both a decreased intravascular oncotic pressure and altered pulmonary capillary permeability. Case 2. A 19year-old black female from Rock Hill, S. C. was seen by her physician two days prior to hospitalization, at which time an upper
903
Walker
and
Mattern
Fig. 2. Photomicrograph of lang from Case 2 of RMSF. Interstitial pneumonia is characterized by mononuclear cell infiltration of the alveolar septa. Proteinaceoas edema fluid fills the alveolar spaces. (Mematoxylin-eosin stain; original magnificatioe X 220).
Fig. 3. Photomicrograph cf lung from Case 2 of RMSF. Brightly immunofluorescent Rickettsia rickettsii are visible within thickened portions of an alveolar septum. (Fluorescein isothiocyanate conjugated anti-R&et&a rickettssii globulin fraction; original magnification X 350.)
respiratory infection was diagnosed and treated symtomaticaliy. Over the next two days she developed nausea, vomiting, high fever, and malaise. Physical examination at the time of admission &owed a blood pressure 80/W mm. Hg and a pulse rate of 100 beats per minute. She was lethargic, and appeared acutely oriented, though ill. Physical examination showed no rash. Scleral icterus was noted but without enlargement or tenderness sf the liver. The lungs were clear to auscultation, and no signs of heart failure were observed. Liver function tests were markedly abnormal with total bilirubin I5 mg./dl., moderately elevated alkaline phosphatase, and markedly elevated liver enzyme values. The BUN was 91 mg./dl. and serum creatinine was 4.8 mg./dl. The serum sodium was 125 mEq./L., serum calcium 6.8 mg./dl., total protein 5.8 g./dl., and albumin 3.1 g./dl. Febrile agglutinins included a Proteus OX 13 titer of 1:2O. Fluids were given as 5% dextrose in water alternating with normal saline at a rate of 3,000 ml. per day, and methylprednisolone was given intravenously I gm. every 8 hours. The blood pressure rose initially, but she remained oliguric and her general condition deteriorated. Thirty-six hours after admission, therapy with tetracycline was begun intravenously 500 mg. every 8 hours. Forty-six ours after admission the patient became agitated and hypotensive. Two hours later a cardiorespiratory arrest
occurred following an episode of vomiting, and the patient could not be resuscitated. Pertinent necropsy findings were multifocal interstitial pneumonitis, bilateral pulmonary edema (Fig. 2) associated with severe rickettsial infection of alveolar capillaries g. 31, mild mononuclear interstitia! myocard and acute tubular necrosis with cortical interstitial edema and lo-w regenerative tubular epithehum. Comment. Although lacking extensive pulmonary clinical and functional data, this patient is an excellent example of the pathologic and rickettsiologic involvement of lungs, heart, and kidneys in RMSF. Despite initiation of tetracycline treatment on her fourth day of illness, she sucAs sugcumbed to a severe rickettsial infection. gested clinically by the persistent oliguria following restoration of blood pressure to normal with intravenous fluids, she had acute tubular necrosis at autopsy. One of the most important manifestations of her diseasewas severe riekettsial infection of the pulmonary microcirculation associated with alveolar edema. Pulmonary edema was documented grossly and microscopically in the face of only mild mononuclear interstitial myoearditis. Based on the pathological changes we have in the heart and lungs, and the limited ta referred to above, it appears that the pulmonary edema seen in RMSF is most often
December,
1980,
Vol.
100, No.
&part
I
Rickettsial
non-cardiogenic. It typically occurs after vigorous fluid administration, usually at the height of illness, and is prolbably a consequence of an increase in pulmonary capillary permeability. Confirmation of the pathogenesis of the pulmonary edema, however, will require more specific physiologic data, including measurements of pulmonary capi.llary wedge pressures, pulmonary capillary oncotic pressures, and pulmonary interstitial oncotic pressures as estimated by the measurement of edema fluid protein concentration.37 Conclusions
The documented changes in systemic capillary permeability, and probable changes in pulmonary capillary permeability which we have discussed, have definite therapeutic implications with reference to intravenous fluid therapy in severely affected patients. The selection of fluids, either colloids or crystalloids, is particularly controversial in terms of predicting the effect on the Starling forces in the pulmonary circulation.38 The use of crystalloids may cause both a small increase in intravascular hydrostatic pressure (PCWP) and, by ‘dilution, a small decrease in intravascular oncotic pressure. The net change in filtration pressure may be sufficient to favor transudation of fluid into the pulmonary interstitium. Colloid administration may cause an increase in pulmonary intravascular hydrostatic and oncotic pressures; but interstitial oncotic pressure may also rise if pulmonary capillary permeability to proteins is sufficiently altered, favoring the development of pulmonary edema.“Y As noted, five of the 13 patients reported by Harrell developed pulmonary edema after colloid was administered at the height of the illness. Among the corrclusions that can be reached with certainty is the fact that pulmonary function is particularly at risk in severe RMSF. Patchy areas of vasculitis and interstitial edema in the kidney or heart may cause little damage to renal tubular transport or myocardial contraction, and in the systemic circulation may not impair flow or peripheral delivery of nutrients (at least until hypotension supervenes). These same pathologic changes in the pulmonary capillaries, on the other hand, may lead to an acute increase in lung water and impairment of gas exchange. The purpose of fluid administration in severe
American
Heart
Journal
uasculitis
rickettsial infections is to expand intravascular volume and support blood pressure so that adequate perfusion of vital organs and peripheral tissues can be maintained during the acute phase of the vasculitis. Care should be exercised to limit fluid administration (1) to avoid the accumulation of peripheral edema, with the attendant risk of subsequent intravascular volume overload as vascular integrity is restored; and, (2) to minimize the risk of developing pulmonary edema, particularly at the height of the illness when pulmonary capillary permeability may be significantly increased. Monitoring of pressures in the pulmonary capillary circulation should be considered in the severely ill patient with hypotension to assist in the selection and use of intravenous fluids. The authors wish to thank Ms. Barbara G. Cain for photographic assistance, Mrs. Jennie Lu Hollander for secretarial assistance, and Dr. James Ma> ‘:ard for providing Case 2 for our study.
REFERENCES
1. 2.
3.
4.
5.
6.
7.
a. 9.
10. 11.
12. 13.
Weiss, E.: Growth and physiology of rickettsiae, Bacteri01. Rev. 37:259, 1973. Bozeman, F. M., Masiello, S. A., Williams, M. S. and Elisberg, B. L.: Epidemic typhus rickettsiae isolated from flying &irrels, Nature 255:545, 1975. Bozeman. F. M.. Elisbers. B. L.. Humnhries. J. W.. Runcik, K., and Palmer, D. B. Jr.: Serologic evidence of Rickettsia canada infection of man, J. Infect. Dis. 121:367, 1970. Annual Summary, 1977. Morbidity and Mortality Weekly Report, HEW Pub. No. (CDC) 78-8241, 26:2, 1978. D’Angelo, L. J., Winkler, W. G., and Bregman, D. J.: Rocky Mountain spotted fever in the United States, 1975-1977, J. Infect. Dis. 7 38:273, 1978. Hattwick, M. A. W., O’Brien, R. J., and Hanson, B. F.: Rocky Mountain spotted fever: epidemiology of an increasing problem, Ann. Intern. Med. 84:732, 1976. Hattwick, M. A. W., Retailliau, H., O’Brien, R. J., Slutzker, M., Fontaine, R. E., and Hanson, B.: Fatal Rocky Mountain spotted fever, J. A. M. A. 240:1499, 1978. Maxey, E. E.: Some observations on the so-called spotted fever of Idaho, Medical Sentinel 7:433, 1899. McCullough, G. T.: Spotted fever, Medical Sentinel 10:225, 1902. Wolbach, S. B.: Studies on Rocky Mountain spotted fever. J. Med. Res. 41 :l, 1919. Peterson, J. C., Overall, J. C., and Shapiro, J. L.: Rickettsial diseases of childhood. A clinical natholosic study of tick typhus “Rocky Mountain spotted fevei,” and murine typhus “endemic typhus,” J. Pediatr. 30:495, 1947. Harrell, G. T.: Rocky Mountain spotted fever, Medicine 28:333, 1949. Stoenner, H. G., Lackman, D. B., and Bell, E. J.: Factors affecting the growth of rickettsias of the spotted fever group in fertile hens’ eggs, J. Infect. Dis. 110:121, 1962.
905
14.
Wolbach, S. B., Todd, J. L., and Palfrey, F. W.: Pathology of typhus in man, in The Etiology and Pathology of Typhus. Being the Main Report of the Typhus Research Commission of the League of Red Cross Societies of Poland, Cambridge, 1922, Harvard University Press, pp.
28.
29.
152-256. 15.
16. 17.
18.
19. 20.
21. 22.
23.
24.
25.
26.
27.
Harrell, G. T., Venning, W., and Wolff, W. A.: The treatment of Rocky Mountain spotted fever with particular reference to intravenous fluids, J. A. M. A. 1 X:929, 1944. Woodward, T. E., and Bland, E. F.: ClinicaP observations in typhus fever, J. A. M. A. 126:287, 1944. Harrell, G., and Aikawa, J.: Pathogenesis of circulatory failure in Rocky Mountain spotted fever, Arch. Intern. Med. 83:331, 1949. Wolbach, S. B.: The pathology of the Rickettsial diseases of man, in Moulton, F. R., ed., Rickettsial Diseases of Man, Washington, 1948, American Association for the Advancement of Science, pp. 118-125. Lillie, R. D.: The pathology of Rocky Mountain spotted fever, Natl. Inst. Health Bull. 177:i, 1941. Walker. D. H.. and Mattern. W. 14.: Acute renal failure in Rocky ’ Mountain spotted’ fever, Arch. Intern. Med. 139443, 1979. Parker, R. R.: Rocky Mountain spotted fever, J. A. M. A. 110:1185, 1938. Moon, J. II., and Silverberg, S. G.: Febrile exanthem in 14-year-old boy with subseqnent development of coagulopathy, Va. Med. Monthly 98:271, 1971. Allen, A. C., and Spitz, S.: A comparative study of the pathology of scrub typhus (tsutsugamushi disease) and other rickettsial disease. Am. J. Pathol. 21:603. 1945. de Brito, T., Tiriba, A., Godoy, C. V. F., Penna, D. O., and Jordbo, F. M.: Glomerular response in human and experimental rickettsial disease (Rocky Mountain spotted fever group). A light and electron microscopy study, Path. Microbial. (Basel) 31:365, 1968. Bradford, W. D., Croker, B. P., and Tisher, C. C.: Kidney lesions in Rocky Mountain spotted fever: a light, immunofluorescence, and electron-microscopic study, Am. J. Patbol. 97:381, 1979. Levine, H. D.: Pathologic study of thirty-one cases of scrub typhus fever with especial reference to the cardiovascular system, AM. HEART J. 31:314, 1946. Gutman, A., Taragan, R., Bernheim, J., et al.: Acute renal failure in spotted fever, Harafuah 89:298, 1975.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
Wilson, L. B., and Chowning, W. M.: Studies in Pyroplasl mosis hominis (“spotted fever” or “tick fever” of the Rocky Mountains), J. Infect. Dis. 1:31, 1904. Settle, E. B., Pinkerton, II., and Corbett, A. J.: A pathologic study of tsutsugamushi disease (scrub typhus) with notes on clinicopathologic correlation, J. Lab. Ch. Med. 30:639, 1945. Bradford, W. D., and Hackel, D. B.: Myocardial involvement in Rocky Mountain spotted fever, Arch. Pathol. Lab. Med. 102:357, 1978. Pincoffs, M. C., and Shaw, C. C.: The eastern type of Rocky Mountain spotted fever. Report of a case with demonstration of rickettsiae, Med. Clin. North Am. l&1097, 1933. Walker, D. PI., Paletta, C. E., and Cain, B. 6.: Pathogenesis of myocarditis in Rocky Mountain spotted fever, Arch. Pathol. Lab. Med. 104:171, 1980. Walker, D. H., Crawford, C. G., and Cain, B. 6.: Rickettsial infection of the pulmonary microcirculation, the basis of interstitial pneumonitis of Rocky Mountain spotted fever, Human Pathology 11:263, 1980. Donohue, J. F.: Lower respiratory tract involvement in Rocky Mountain spotted fever, Arch. Xntern. Med. 140:223, 1980. Walker, D. H., Cain, B. G., and Clmstead, P. M.: Laboratory diagnosis of Rocky Mountain spotted fever by immunofluorescent demonstration of Rickettsia rickettsii in cutaneous lesions, Am. J. Clin. Pathol. 69:619, 1978. Woodward, T. E., Pedersen, C. E., Jr., Oster, C. N.; Bagley, L. R., Romberger, J. and Snyder, M. J.: Prompt confirmation of Rocky Mountain spotted fever. Identification of rickettsiae in skin tissues, J. Infect. Dis. -l34:297, 1976. Fein, A., Grossman, R. F., Jones, J. G., Overland, E., Pitts, L., Murray, 9. F., and Staub, N. C.: The value of edema fluid protein measurement in patients with pulmonary edema, Am. J. Med. 67:32, 1979. Shoemaker. W. C.. and Hauser. 6. J.: Critiaue of crvstalloid versus’ colloid therapy in sllock and shock “lung, Critical Care Med. 7:117, 1979. Stein, L., Beraud, J., Morissette, M., daLuz, P., Weil, M. H., and Shubin, H.: Pulmonary edema during volume infusion, Circulation 52:483, 1975.
December,
1980,
Vol.
100,
No.
6, part
I
William
vasculiti
Walker, M.D.* D. Mattern, M.D.**
Chapel Hill, 7% C.
Important rickettsial diseases of man are distributed over all the continents with the exception of Antarctica. In order to approach these diseases, their etiologic agents must be defined taxonomitally. Definition of the term rickettsia varies from a nearly meaningless inclusiveness of almost any intracellular microorganism to a narrower consideration of only the genus Rickettsia. In this discussion, the other related genera Coxiella ( fever) and Rochalimaea (trench fever), will be excluded. Members of genus Rickettsia share the following characteristics: gram negative bacterial ultrastructural morphology, obligate intracellular parasitism, ecologic niche including all or a portion of life spent in an arthropod host, and serologic grouping relationships. There are three serologic groups: typhus group, spotted fever group, and scrub typhus group. The concept that rickettsiae are an intermediate form of life between viruses and bacteria is completely outmoded. That they are clearly a specialized group of bacteria is confirmed by method of replication (binary fission), content of both RNA and DNA, ultrastructural morphology, and sensitivity to antimicrobial agents.’ Although rickettsiae are capable of penetrating and growing witbin a wide variety of host cells of various species and organ sources, in man they are found only in vascular endothelium and, in some diseases, vascular smooth muscle. This anatomic distribution determines the basically similar pathology (vasculitis) From North Received
the Departments Carolina School for publication
of Pathology and Medicine, University of Medicine, Chapel Hill, N. C. Nov.
14, 1979.
Reprint of North
requests: Carolina,
Dr. David H. Walker, School of Medicine,
Dept. of Pathology, University Chapel Hill, N. C. 27514.
*Dept. cine.
of Pathology,
University
of North
Carolina
School
of Medi-
**Dept. cine.
of Medicine,
University
of North
Carolina
School
of Medi-
896
December,
1980, Vol. 100, No. 6, part
1
of
and pathophysiology (increased vascular ability) of the rickettsial diseases. Geographic distribution of rickettsial diseases reflects the distribution of infected arthropod hosts and their contact with man. Rickettsial diseases of man, their etiologic agents, vectors, and geographic distribution are resented in Table I. Although other rickettsiae have been discovered in various econiches in the United States, at this time only Rickettsia rickettsii (Rocky Mountain spotted fever), Rickettsia mooseri (murine typhus), Rickettsia prowazeki (recrudescent typhus), and Rickettsia czkari (rickettsialpox) have been documented as etiologic agents of disease in man in recent times. Evidence indicates that epidemic typhus has probably been transmitted to man from a natural zoonotic cycle of Rickettsia prowazeki in flying squirrels in the southeastern states? and that Rickettsia canada possibly causes a diseasesimilar to Rocky Mountain spotted fever.” Mowever, in current reports Rocky Mountain spotted fever (RMSF) accounts for more than 90% of rickettsial disease,with murine typhus a distant second in incidence and the others apparently quite rare.’ The incidence of RMSF has risen to a kigh level with continued significant mortality. In 1959 only 199 caseswere reported, and by 1968 the annual total was still only 298 cases. Since that time a remarkable increase has occurred, peaking at a total of 1,153 cases in 1977.5 Expressed as rates this is a rise from 0.11 cases per 100,000 population in 1959 to 0.50 cases per 100,000 nationally and 1.66 cases per 100,000 in the South Atlantic states in 1977. Although the mortality rate has fallen from 20% in the preantibiotic era, it has remained in the 5 to 10%range to the present time despite the efficacy of tetracycline and chlorampbenicol. RMSF has been reported from 46 0002-8703/80/120896
+ 11$01.10/O
0 1980
The
6. V. Mosby
Co.
Rickettsial
Table
vasculitis
I Disease
/Etiology
Typhus group Epidemic typhus
Vector
Geographic
distribution
R. prowazeki
Louse
R. prowazeki
Ectoparasite of flying squirrels None
Murine typhus Spotted Fever group Rocky Mountain spotted fever Old-world tick-borne spotted fever (Bou-. tonneuse fever, South African tick.. bite fever, Kenya typhus, etc.) Siberian tick typhus Queensland tick typhus Rickettsialpox
R. mooseri
Rat
R. rickettsii
Tick
R. conori
Tick
U. S., especially southeastern Brazil, Colombia, Mexico, Mediterranean basin, Africa,
R. sibirica R. australia
Tick Tick
Siberia Australia
R. akari
Mite
Central European tick typhus Scrub Typhus group Scrub typhus
R. slovaca
Tick
Probably worldwide; documented U. S. S. R. Central Europe, Armenia
R. tsutsugamushi
Mite
Eastern
Recrudescent
typhus
flea
states; however, there is a higher incidence in the southeastern states with North Carolina, Virginia, Tennessee, Oklahoma, South Carolina, Georgia, and Maryland reporting 66.1% of all cases between 1975 and 1977.5Casesoccur most often in children, in males, and between mid-April and mid-September. Moreover, mortality rates are higher for adults (over age 30, 13.9% vs. 5.4% under age 30), males (8.2% vs. 4.5% in females), and nonwhites (13.9% vs. 5.8% in whites): Fatal cases seek medical attention at the same time during the course of illness as nonfatal cases. However, their rash appears later; they give a history of tick bite less often or later in the course; and initial or unexpected symptoms lead to misdiagnosis. As a result of incorrect or delayed diagnosis, antirickettsial treatment is not given or is given too late to be effective.7 Effect
of rickettsiae
on the
microcirculation.
Dermal involvement in rickettsial diseasesis not only a prominent clinical sign but also an opportunity to observe and evaluate the nature of the American
Heart
Journal
Historic: all continents except Australia Recent: Burundi, Rwanda, Uganda, Ethiopia, Algeria, Chad, Niger, Zambia, Nigeria, Zaire, Liberia Bolivia, Peru, Ecuador, Chile, Guatemala, Costa Rica, Mexico Southeastern U. S.
Worldwide, especially localities of previous typhus demics, eg., Poland and Yugoslavia; or countries migration of previous typhus cases, eg., U. S. and Canada Worldwide, especially in warmer climates including
and southern
Asia
states; Panama Asia
western
in cities
and southwestern
epiof im-
U. S.
Canada,
of U. S. and
Pacific
vascular events. The observations indicate that the microcirculation is the primary target, with variable subsequent contiguous centripetal extension to arteries and veins. The temporal sequence of events which may be seen in the skin of patients with typhus and RMSF reflects the pathologic and pathophysiologic events in these diseases. The rash of RMSF is delayed, usually occurring three days after onset of fever with a range of 2 to 7 days and rarely not appearing at all.*-” The rash tends to appear first on ankles, feet, wrists, and hands, and to spread centripetally to involve the entire body within 24 to 36 hours, usually including the palms and soles. This centripetal spread contrasts with the centrifugal spread of the rash of typhus. The difference has never been satisfactorily explained, although optimal growth of Rickettsia rickettsii at lower temperaturesI would favor earlier attainment of a critical mass of pathogenic organisms in peripheral sites. Initially, the rash consists of pink, unelevated 897
Walker
and
Mattern
macules which are from less than one to five millimeters in diameter, blanch co temporarily on pressure, and are Subsequently these lesions acquire a deep to-purple hue and increase in size, e confluent in some cases. onset, the rash becomes chial. In severe cases during the third week necrosis of dependent peripheral parts, including scrotum, prepuce, fingers, toes, and external ear may occur. Study of the pathologic lesions in rickettsial disease has been performed most comprehensively in epidemic louse-borne typhus. Wolbach, who already had extensive experience in investigating RMSF, was sent to Poland with the Typhus Research Commission during World War I[. descriptions based on the stu y of skin from 36 necropsies and skin biopsies from 28 patients covered the range from the first day of rash to the twenty-fourth day of disease.l” At the onset sf rash (day 3 of disease), the only pathologic lesion was “swelling of the endothehum of capillaries and small arteries and veins” of the papillary an reticular dermis. Rickettsiae were observed in swollen endothelial cells. On day 5 of the disease, arterioles an venules demonstrated mural ng swollen endothehal cells which frequently contained numerous rickettsiae. vascular reaction was minimal. Subsequently contiguous spread of rickettsiae with accumulation of increased quantity of organisms was observed in serial sections; moreover, the pathologic lesions involved larger vessels in the deep dermis and subcutaneous tissue nt perivascular memo ermal hemorrhages were ob aries and vessels of size” on and after the eighth day of illness. Organization of vascular tbrombi was seen as early as the fifteenth day. Areas of gangrene were demonstrated microscopically not to be aceo panied by thrombosis of large vessels but to due to thrombosis of capillaries and small arternes and veins beginning in the dermis and extending centripetally. Comparison of the lesions of typhus and RMSF is most remarkable for their similarity. owever, differences which comprise more extensive destruction of the vascular wall including the media and less pronounced perivascular inflammation in RMSF reflect infection of vascular smooth
muscle by Rickettsia rickettsii and not ~~~~et~~~~ prowazeki and the generally shorter course of fatal casesof RMSF. “Rarely in any disease are the pathologic Iesions correlated so closely with the clinical picture . . f A careful study of the patient’s clinical record will reveal a very close correlation between the microscopic findings and the physiologic disturbances, although the latter may be out of all proportion to the visible anatomic lesions.‘912 These comments by Hare11in his review of in 1949 certainly apply to the physiologic bances in the peripheral circulation in the nmre severe rickettsial infections such as epidemic typhus, scrub typhus, and RMSF. Hn 1944 reP1,referring to RMSF,‘” and Woodward ring to epidemic typhusYxGpostulated in separate publications that hypotension and circulatory collapse seen at &e height of these rickettsial infections resulted not from “cardiac weakness,” but from peripheral circulatory failure, the latter resulting from a decrease in blood volume as a consequence of an increase in systemic capillary permeability. They both noted that the falhng blood pressure at the height of the illness coincided with the appearance of edema and with a concentration of serum proteins, particn a more detailed investigation of the pathophysiology of the peripheral circulatory failure 9n RMSF, Harrell in 1949 reported serial observations in 13 patients.‘? The entire natural bistory of the illness was observed, since neither tetracycline nor chloramphenicol was, then available as specific treatment. Sequential measurements of plasma volume (using Evans Blue dye), “extravascular volume” (using thiocyanate space), and the serum concentrations of total protein, albumm, nonprotein nitrogen (NPN), an were correlated with various chnica tions, and the effect of intravenous therapy with crystalloid-and colloid-containing solutions was noted. The illness was considered mild if the tourniquet test was negative, there was no e and the pulse and blood pressure were stable; moderate if the tourniquet test was positive, the was slight edema, the pulse rate was increas and the patient appeared toxic; an severe if there were purpura, marked edema, and delirium. Cases with a fulminant clinical course were not included. Data were summarized for the moderate to severe cases at three stages: (I) soon after
December,
1980, Vd. 100, No. 6, part
1
Rickettsial
onset of the rash, (2) at the height of illness 9 to 14 days after onset of the rash, and (3) during the recovery period in the third week after onset of the rash. Patients presented shortly after the appearance of the rash with clinical signs of dehydration, an elevated NPN and low serum chloride concentration, a normal or slightly low serum protein concentration and plasma volume, a normal thiocyanate space, and a low normal blood pressure. When intravenous therapy with crystalloid solutions was given in an effort to correct the dehydration at this point in the illness, there was a prompt fall in the NPN and a rise in serum chloride concentration. Plasma volume rose transiently, and there ‘was a reciprocal fall in the serum protein concentration. If crystalloid solutions were continued, the expansion of plasma volume was sustained and there was a striking rise in the thiocyanate space, coinciding with the development of progressive peripheral edema. At the height of the illness, the onset of hypotension was associated with a more marked reduction in the serum protein concentration and plasma volume, elevated thiocyanate space, and peripheral edema. Crystalloid administration at this point accelerated the extravascular accumulation of fluid with’out a favorable effect on the blood pressure or plasma volume. The onset of recovery was marked by return of temperature to normal and a reversal of the above abnormalities. The blood pressure rose to normal as plasma volume began to increase. The thiocyanate space gradually decreased as edema was mobilized and diuresed; and finally, the serum protein concentration returned to normal. The administration of colloid solutions, such as plasma or albumin, in contrast to crystalloids, did support the blood pressure and plasma volume at the height of illness and early in the recovery period, but in five of the six instances reported its administration also precipitated acute pulmonary edema. These findings were interpreted to indicate that the vasculitis of RMSF led to a progressive increase in systemic capillary permeability such that there was a gradual loss of protein from the vascular compartment and a decrease in intravascular oncotic pressure. Although this study served to characterize the sequential changes in systemic capillary permeability in the more severe cases, it left unanswered important questions about fluid therapy, and also raised
American
Heart
Journal
vasculitis
basic questions about cardiac function pulmonary capillary function in RMSF.
and
Renal pathology in rickettsial diseases. The path.ologic lesions of kidneys in rickettsial diseasesmay be considered to be either of two types: lesions due to local effects of rickettsiae on renal vessels or lesions due to the effects of systemic hypovolemic shock. In studies of typhus fever, Wolbach described focal lesions in which “only small blood vessels are affected and. . . the cellular response is infiltrative.“‘” These lesions contained capillaries or precapillary blood vessels surrounded by mononuclear phagocytes, lymphocytes, plasma cells, and polymorphonuclear leukocytes and incorporated one or several tubules in various stages of injury up to actual necrosis. Wolbach noted that these lesions were present also in scrub typhus and Rocky Mountain spotted fever, but that in all three diseases the distribution was spotty and little renal parenchyma was involved.18 In the classic description of the pathology of RMSF, Lillie observed that 12 of 17 caseshad focal lesions with “irregular interstitial and perivascular infiltration by lymphocytes, in later cases offten plasma cells and large lymphoid cells as we11.“19These lesions were especially marked at the corticomedullary junction. Focal pericapillary and interstitial hemorrhages were identified in six cases. Our study confirmed these observations and demonstrated by specific immunofluorescence that the distribution of the majority of the Rickettsia rickettsii was identical with that of the multifocal perivascular interstitial nephritis, concentrated near the corticomedullary junction.20 Another potential local effect of rickettsial infection on the kidney is thrombosis. Wolbach described precisely this relationship in typhus fever with thrombosis of vessels in the focal interstitial lesions, no lesions of large blood vessels, and one case with small mural thrombi in small arteries of the pelvic submucosa with rickettsiae in the endothelium of the affected vessels.14Our original study of ten cases of RMSF with histochemical staining for fibrin revealed thrombi only in vessels of a minority of the focal interstitial lesions and no glomerular thrombi.20 Subsequently we have investigated a case of fuLminant RMSF (defined by ParkerZ1 as fatal within 3 to 5 days of onset) which showed fibrin thrombi in approximately half of the glomeruli. Glomerular fibrin thrombi were also demon-
899
strated in the only case of f~lmin~~t RMSF with description of pathology reported in the literature2* Pn our case, study of serial sections stained for fibrin histochemically and for ettsik imm~~oh~tochemica~~y demonstrated that thrombotic glomeruli were intensely infected and that ~onthrombotic glomeruh were mi~~rna~ly or mildly infected. In an intermediate position, several recent cases with death occurring on day 6 or 7 of disease have had rare focal gl~merular tbrombi. hese observations on throm tissue from rickettsial diseases indicate that thrombosis is the response to local injury to blood vessels by rickettsiae. Two lesions which could be due to local an systemic effect of rickettsial infections are merulonephritis and edema of tb is no consensus that glomerulon occurs in rickettsial diseases. Gl was described by Allen and Spit9 in scru hus and RMSF. Ultrastru renal biopsies from five razilian cases of RMSF with various degrees of acute renal funcment demonstrated no g~orner~~o~eonly nonspecific endothelial swelling cells.*” Our cases, controlled tbickment membranes revealed no ~~orneruione~h~t~s~ a5 judged by the absence of glomerular hype~cei~~~a~ty and b ment membrane lesions. Another recent st has shown no glomerular immune complexe ~mnnofluore5cence and no ltrastructural deposits. On the other han increased renal weights, presumably secondary to edema, have ported in some cases of scrub typhus*” and 20 This edema may result from multifocal vasculitis and/or acute tubular necrosis. significant pathologic sion which is the of systemic shock on t kidneys is acute tubular necrosis (ATN). In two of 37 cases of typhus fever, heavy kidneys with pa cortices were compatible Although ATN is not alway logically in all of its time-course and autolysis often renders tubular epithehum impossible to evaluate microscopically, the stage sf ATN idenkedly thin tubular epithelium and ma has been observed in cases of hysiology
in ?~c~e~~s~a~ diseases.
With reference to clinical abnormalities of renal
function, the remote effects of the systemic vascuhtis far outweigh the effects of the observed intrarenal pathology and can best be understood as the sequential manifestations of altered systemic capillary permeability.‘0 Interestingly, the basic renal lesion, a focal, perivascular interstitial nephritis, finds little clinical expression. Early in the course of the more severe rickettsial infections, patients often present with dehydration, a moderately elevated BUN and serum creatinine concentration, mild hyponatremia teinemia, a low-normal blood pressu gressive hypovolemia. The BUN is relation to the serum creatinine ~o~ce~trat~o and the urine volume is reduced, though usual not to oliguric levels. There is a trace to i c proteinuria by reagent stick, and 24hour collections contain less than 500 mg. of protein. The urine sediment contain5 a few coarsely granular casts, but no increase in cellular elements The urine specific gravity is usually greater than 1.020 and urine sodium concentration is low, often less than 10 mEq./L. Expansion of intravascular volume with colloid or crystalloid solutions restores renal function to normal within a few days. This entire picture is consistent with prerenal azotemia. At the height of illness, in severe cases wit otracted course, acute hypotension te oliguric acute renal failure (A Despite prompt restoration of blood pressu normal and maintenance of intravasular volume, the oliguria persists. The urine c sediment are typical of ATN. ATN, in this setting, has been reported in boutonneuse fever, a milder, but related rickettsial infectionz7 but not to date in Rocky Mountain spotted fever, although the potential for recovery has been demonstrated. Oliguric acute renal failure is a regular occurrence in fulminant cases, in association with systemic circulatory collapse. Causes other than hypotension have been considered in the pathogenesis of ATN in Rocky Mountain spotted fever, specifically non~tra~matic rhabdomyolysis with myoglobinuria, but evidence to support their occurrence is lacking. As noted, histologic lesions of acute diffuse glomerulonephritis were described in one early report of RMSF. A review of published casesand our own material, however, does not reveal other documentation of this lesion, and there is no clinical data (heavy proteinuria, hematuria with
December,
1980, Vol. IN?, No. 6, part
2
Rickettsial
red cell casts) to support the occurrence of acute glomerulonephritis. Thus, the major clinical abnosrmalities in renal function, prerenal azotemia and ATN, are the early or later consequences of tbe systemic vasculitis. Recovery of renal function with prerenal azotemia is the rule, and the potential for recovery from ATN with resolution of the vasculitis is suggested. Cardiovascular and pulmonary pathology rickettsial diseases. In general, the heart
in
in typhus fever, RMSF, and scrub typhus manifests negligible gross alterations and. virtually universal microscopic interstitial mononuclear myocarditis. Wolbach felt that inflammatory infiltration of the myocardium was diffuse because of its relationship to the most diffusely distributed blood vessels, the capillaries; that the order of severity of inflammatory infiltration was scrub typhus, typhus, and RMSF; and that not much evidence of degeneration of heart muscle could be demonstrated.‘s Myocarditis was noted in a series of eight autopsies of cases of RMSF by Wilson and Chowning in 1904.‘” They noted a few epicardial petechiae, dark, fluid blood filling the right ventricle, empty left ventricle, and “considerable round cell infiltration.” Following a number of case reports by a series of authors often citing myocarditis, Lillie published the classic description of myocarditis in RMSF in his series of I7 cases.lgGrossly, he noted that “the right ventricle was more often dilated than the left, but in the majority the status of the chambers was ‘normal’ or contracted” and that “altogether gross changes were slight.” Microscopically, two cases were normal; 15 manifested “interstitial infiltration of variable density, chiefly by lymphocytes, often with lesser numbers of plasma cells, monocytes . . _a few neutrophil or eosinophil leukocytes or mast cells.” Myocarditis was “irregular and patchy. . . often distinctly centered about small vessels and in interfascicular connective tissue.” Only two cases had focal coagulative necrosis of myocardial cells. In the definitive study of the pathology of typhus, Wolbach stated that “as a rule the left ventricle was contracted and the right moderately dilated.“‘* In six postmortem examinations performed soon after death in cases without significant bacterial complications, myocardium showed pallor, loss of consistency, and yellowish streaks and points. Acute valvular lesions and
American
Heart
Journal
uasculitis
macroscopic mural thrombi were not detected. Microscopic lesions, which were observed in all 37 necropsies, included slight degrees of edema, focal and diffuse myocarditis with interstitial macrophages, lymphocytes, plasma cells, few polymorphonuclear leukocytes, and vascular lesions “almost wholly restricted to capillaries and vesselsof pre-capillary size.” Large blood vessels in the heart and pericardium very rarely contained lesions. Pathologic studies of the heart in scrub typhus have yielded essentially the same observations as in typhus fever and RMSF.‘“, 29 Besides myocarditis, there have been few consistent pathologic alterations of the heart in the rickettsial diseases. When present they have included few subendocardial mononuclear inflammatory foci, pericardial fluid varying from none to moderate to rarely large amounts, and an occasionally demonstrated focal inflammatory lesion involving a conduction bundle3” or the Purkinje conduction system. The relationship of rickettsiae to the myocarditis has been unclear. Much of this unsatisfactory state has been a result of the unreliability of the various Giemsa techniques to demonstrate rickettsiae. Even in the hands of Wolbach, who used the method to demonstrate rickettsiae successfully in many lesions of typhus and spotted fever, rickettsiae could not be satisfactorily demonstrated in heart lesions of typhus fever.14 Of 40 cases of RMSF in which Giemsa stain was reported to have been used to search for rickettsiae in heart, only a single case was reported to contain rickettsiae “within the cytoplasm of the endothelial cells of the subepicardial and interstitial capillaries.““’ In contrast, Rickettsia rickettsii were demonstrated in hearts of all eight untreated or inadequately treated casesof RMSF which were examined by a technique of deparaffinization, trypsin digestion, and specific direct immunofluorescence in our laboratory.32 Rickettsia rickettsii were observed in capillaries, venules, arterioles, and large vessels including coronary arteries in descending order of invlolvement. Vascular infection with resultant vascular injury and increased permeability provides the probable pathogenetic mechanism for moderate myocardial edema. Data on the same series of hearts with etiologically confirmed RMSF which suggested myocardial edema were increased heart weight in eight of nine casesand detectably increased interstitial volume in six of
901
nine cases.3z Absence of left ventricular dilatation indicated that severe myocardial failure was not the etiology of hypotension, shock, and death in Pathologic studies of lung in rickettsial disease have demonstrated interstitial pneumonitis with alveolar walls containing mononuclear ieukocytic infiltration.‘*~ lR. lg. z3.26.2e.33 In cases which were heated by broncbo~~eumo~ia, interstionitis was manifested grossly by congestion and edema. Further microscopic evi for loss of vascular integrity are multiple foci of alveolar hemorrhage, fibrin, and edema. Examination of lungs from cases of immunofluorescence has revealed moderate-tosevere infection of the pulmonary microcirculation by ~~~kett~i~ rick&&ii (see illustrative Case 2 below), thus providing a pathogenetic expdanation for the interstitial pneumonitis and the increased pulmonary vascula
referred to convincingly exclude any significant contribution by the heart to the development of hypotension and peripheral circulatory collapse in the course of severe rickettsial infection; but the role of the heart in the development of pulmonary edema, a less common complication, has been more difficult to elar “typhus beart,” et that “central circu and pulmonary edema were distinctly uncommon.‘” None of the 30 severely or critically ill patients he studied during the course of their illness had cardiac erdargement y physical examination, a gallop rhyth istended neck veins, or an enlarged liver. e recorded serial measurement of venous pressure. Values above 12 cm. water were not seen, and the average value was 8 cm. water. Radiographs were available in 12 patients and showed neitber eardiomegaly nor conjestion. electrocardiograms no striking deviations from normal. Rales were heard frequently, but usually in association with coarse rhonchi, and were considered to be ma~~festati~~s of tracheobronchitis or patchy bron~bo~~e~mon~a~ both of which were often observed at neeropsy. Pulmonary edema has occasionally been noted in scrub typhus, but not in conjunction with other findings of heart failure. Th critically ill or preterminal, and t
edema was considered to be a manifestation of severe rickettsial pneumonitis.‘“~ 29 Pulmonary edema has been most ~~e~~e~t~y reported in RMSF, and its pathogenesis is of criticaE importance with regard to fluid management. A careful review of the case reports of the 13 patients HarrelS. originally described in his study of peripheral circulatory failure reveals that five developed pulmonary edema during the course of their illness.17 The episodes of pulmonary edema all occurred in the second week of the illness, at the height of the changes in systemic capillary permeability, or a few days into the recovery period. The administration of solutions containing eolloid immediately preceded the development of pulmonary edema in each instance, and an increase in plasma volume was documented by the Evans method. Distended neck veins were not however, and the one recording of venous pressure during of pulmonary edema revealed a value 20. A gallop rhythm was noted in only one instance. Treatment consisted of digitalis administration and fluid restriction. There was clinical resolution of the pulmonary edema within 48 hours in four of the patients, patient developed bacterial pneumonia and died. A recent clinical study of the pulmonary manifestations in RMSF confirms and extends these observations.3’ The records of all patients at one hospital documented to have RMSF between 1973 and 1976 were reviewed. Nine of the 33 patients had deterioration in pulmonary function during the first week of hospitalization, with a widening of the alveolar-arterial oxygen difference. Seven developed radiographic infiltrates, and six developed pulmonary edema. All nine were in markedly positive fluid balance, and four had received large amounts of Auid following hypotensive episodes. None of the patients had third heart sounds, cardiac enlargement ra graphically, or electrocardiographic changes. One of the patients with severe diseasedied withm 24 hours of hospitalization. Diuresis in the other eight patients led to prompt improvement of gas exchange. Radiographic and clinical signs of pulmonary edema cleared within 48 hours. Sinee 1976 we have seen two additional cases, one which illustrates the clinical presentation of pulmonary involvement in RMSF and the other which highlights the pathological changes
Rickettsial
1. Chest radiographs in Case 1 of RMSF. On the day of admission pattern are normal. After two days of parenteral fluid administration radiologic pattern of pulmonary edema is present Fig.
Illustrative
cases
Case 1. A 48-year-old white housewife from Smithfield, N. 6. removed a tick from her scalp ten days before admission. Three days later she developed severe headache, nausea, and fever. Thereafter she had daily fevers of 40°C. and intermittent vomiting. Three days before admission a red macular rash was noted on the trunk and extremities, including the palms and soles. She was admitted to North Carolina Memorial Hospital on September 8,1978. Physical examination showed a blood pressure of 140180 mm. Hg and a temperature of 40°C. Pulse rate was 100 beats per minutes. She was oriented and alert, but appeared weak an.d acutely ill. A generalized maculopapular rash with petechial areas was noted on the trunk and extremities. The lungs were clear, the neck veins were not distended, and examination of the heart showed no enlargement or gallop rhythm. There was no peripheral edema, no adenopathy, and the neurological examination was normal. Blood chemistries included sodium 133 mEq./L., BUN 15 mg./dl., creatinine 0.8 mg./dl., calcium 8.6 mg./dl., total protein 6.5 g./dl., and albumin 3.5 g./dl. The hematocrit was 32% and the platelet count 92,OOO/pl. The prothrombin time and. partial thromboplastin times were normal. The initial chest radiograph (Fig. 1) was interpreteld as normal. A skin biopsy on the day of admission examined by specific direct immunofluorescence was diagnostic for Rocky rickettsii Mountain spotted fever with Rickettsia in dermal blood vessels.““, 36 She was begun on treatment with intravenous chloramphenicol, 100 mg. every 8 hours, and
American
Heart
Journal
(leffj, heart (right),
vasculitis
size and pulmonary vascular heart size is unchanged, but
intravenous hydration with 5% dextrose in normal saline at a rate of 75 ml./hr. On the second day after admission she developed progressive shortness of breath over a period of several hours. Examination revealed diffuse rdles, but the neck veins were not distended and no gallop rhythm was heard. The blood pressure was 160/80 mm. Hg. Arterial blood gases revealed pH 7.52, PCO, 22 torr, and PO, 30 torr. Repeat serum total protein was 6.5 g./dl. with albumin 3.0 g./dl. The electrocardiogram showed sinus tachycardia and nonspecific ST segment changes. A repeat chest radiograph was interpreted as showing pulmonary edema (Fig. 1). She was transferred to the intensive care unit where she was treated with oxygen, furosemide, and digoxin. Within three days pulmonary gas exchange had improved, and the rales and pulmonary infiltrate on chest radiograph had cleared. Her recovery was uneventful. Comment. Fluid administration in this otherwise stable patient led to the abrupt development of pulmonary edema in the absence of signs of heart failure or elevated systemic venous pressure. The predominance of infiltrates in the upper lobes is similar to that seen when pulmonary capillary wedge pressure is elevated-i.e., in cardiogenic pulmonary edema-but might have occurred at only slightly increased pulmonary capillary wedge pressure in the presence of both a decreased intravascular oncotic pressure and altered pulmonary capillary permeability. Case 2. A 19year-old black female from Rock Hill, S. C. was seen by her physician two days prior to hospitalization, at which time an upper
903
Walker
and
Mattern
Fig. 2. Photomicrograph of lang from Case 2 of RMSF. Interstitial pneumonia is characterized by mononuclear cell infiltration of the alveolar septa. Proteinaceoas edema fluid fills the alveolar spaces. (Mematoxylin-eosin stain; original magnificatioe X 220).
Fig. 3. Photomicrograph cf lung from Case 2 of RMSF. Brightly immunofluorescent Rickettsia rickettsii are visible within thickened portions of an alveolar septum. (Fluorescein isothiocyanate conjugated anti-R&et&a rickettssii globulin fraction; original magnification X 350.)
respiratory infection was diagnosed and treated symtomaticaliy. Over the next two days she developed nausea, vomiting, high fever, and malaise. Physical examination at the time of admission &owed a blood pressure 80/W mm. Hg and a pulse rate of 100 beats per minute. She was lethargic, and appeared acutely oriented, though ill. Physical examination showed no rash. Scleral icterus was noted but without enlargement or tenderness sf the liver. The lungs were clear to auscultation, and no signs of heart failure were observed. Liver function tests were markedly abnormal with total bilirubin I5 mg./dl., moderately elevated alkaline phosphatase, and markedly elevated liver enzyme values. The BUN was 91 mg./dl. and serum creatinine was 4.8 mg./dl. The serum sodium was 125 mEq./L., serum calcium 6.8 mg./dl., total protein 5.8 g./dl., and albumin 3.1 g./dl. Febrile agglutinins included a Proteus OX 13 titer of 1:2O. Fluids were given as 5% dextrose in water alternating with normal saline at a rate of 3,000 ml. per day, and methylprednisolone was given intravenously I gm. every 8 hours. The blood pressure rose initially, but she remained oliguric and her general condition deteriorated. Thirty-six hours after admission, therapy with tetracycline was begun intravenously 500 mg. every 8 hours. Forty-six ours after admission the patient became agitated and hypotensive. Two hours later a cardiorespiratory arrest
occurred following an episode of vomiting, and the patient could not be resuscitated. Pertinent necropsy findings were multifocal interstitial pneumonitis, bilateral pulmonary edema (Fig. 2) associated with severe rickettsial infection of alveolar capillaries g. 31, mild mononuclear interstitia! myocard and acute tubular necrosis with cortical interstitial edema and lo-w regenerative tubular epithehum. Comment. Although lacking extensive pulmonary clinical and functional data, this patient is an excellent example of the pathologic and rickettsiologic involvement of lungs, heart, and kidneys in RMSF. Despite initiation of tetracycline treatment on her fourth day of illness, she sucAs sugcumbed to a severe rickettsial infection. gested clinically by the persistent oliguria following restoration of blood pressure to normal with intravenous fluids, she had acute tubular necrosis at autopsy. One of the most important manifestations of her diseasewas severe riekettsial infection of the pulmonary microcirculation associated with alveolar edema. Pulmonary edema was documented grossly and microscopically in the face of only mild mononuclear interstitial myoearditis. Based on the pathological changes we have in the heart and lungs, and the limited ta referred to above, it appears that the pulmonary edema seen in RMSF is most often
December,
1980,
Vol.
100, No.
&part
I
Rickettsial
non-cardiogenic. It typically occurs after vigorous fluid administration, usually at the height of illness, and is prolbably a consequence of an increase in pulmonary capillary permeability. Confirmation of the pathogenesis of the pulmonary edema, however, will require more specific physiologic data, including measurements of pulmonary capi.llary wedge pressures, pulmonary capillary oncotic pressures, and pulmonary interstitial oncotic pressures as estimated by the measurement of edema fluid protein concentration.37 Conclusions
The documented changes in systemic capillary permeability, and probable changes in pulmonary capillary permeability which we have discussed, have definite therapeutic implications with reference to intravenous fluid therapy in severely affected patients. The selection of fluids, either colloids or crystalloids, is particularly controversial in terms of predicting the effect on the Starling forces in the pulmonary circulation.38 The use of crystalloids may cause both a small increase in intravascular hydrostatic pressure (PCWP) and, by ‘dilution, a small decrease in intravascular oncotic pressure. The net change in filtration pressure may be sufficient to favor transudation of fluid into the pulmonary interstitium. Colloid administration may cause an increase in pulmonary intravascular hydrostatic and oncotic pressures; but interstitial oncotic pressure may also rise if pulmonary capillary permeability to proteins is sufficiently altered, favoring the development of pulmonary edema.“Y As noted, five of the 13 patients reported by Harrell developed pulmonary edema after colloid was administered at the height of the illness. Among the corrclusions that can be reached with certainty is the fact that pulmonary function is particularly at risk in severe RMSF. Patchy areas of vasculitis and interstitial edema in the kidney or heart may cause little damage to renal tubular transport or myocardial contraction, and in the systemic circulation may not impair flow or peripheral delivery of nutrients (at least until hypotension supervenes). These same pathologic changes in the pulmonary capillaries, on the other hand, may lead to an acute increase in lung water and impairment of gas exchange. The purpose of fluid administration in severe
American
Heart
Journal
uasculitis
rickettsial infections is to expand intravascular volume and support blood pressure so that adequate perfusion of vital organs and peripheral tissues can be maintained during the acute phase of the vasculitis. Care should be exercised to limit fluid administration (1) to avoid the accumulation of peripheral edema, with the attendant risk of subsequent intravascular volume overload as vascular integrity is restored; and, (2) to minimize the risk of developing pulmonary edema, particularly at the height of the illness when pulmonary capillary permeability may be significantly increased. Monitoring of pressures in the pulmonary capillary circulation should be considered in the severely ill patient with hypotension to assist in the selection and use of intravenous fluids. The authors wish to thank Ms. Barbara G. Cain for photographic assistance, Mrs. Jennie Lu Hollander for secretarial assistance, and Dr. James Ma> ‘:ard for providing Case 2 for our study.
REFERENCES
1. 2.
3.
4.
5.
6.
7.
a. 9.
10. 11.
12. 13.
Weiss, E.: Growth and physiology of rickettsiae, Bacteri01. Rev. 37:259, 1973. Bozeman, F. M., Masiello, S. A., Williams, M. S. and Elisberg, B. L.: Epidemic typhus rickettsiae isolated from flying &irrels, Nature 255:545, 1975. Bozeman. F. M.. Elisbers. B. L.. Humnhries. J. W.. Runcik, K., and Palmer, D. B. Jr.: Serologic evidence of Rickettsia canada infection of man, J. Infect. Dis. 121:367, 1970. Annual Summary, 1977. Morbidity and Mortality Weekly Report, HEW Pub. No. (CDC) 78-8241, 26:2, 1978. D’Angelo, L. J., Winkler, W. G., and Bregman, D. J.: Rocky Mountain spotted fever in the United States, 1975-1977, J. Infect. Dis. 7 38:273, 1978. Hattwick, M. A. W., O’Brien, R. J., and Hanson, B. F.: Rocky Mountain spotted fever: epidemiology of an increasing problem, Ann. Intern. Med. 84:732, 1976. Hattwick, M. A. W., Retailliau, H., O’Brien, R. J., Slutzker, M., Fontaine, R. E., and Hanson, B.: Fatal Rocky Mountain spotted fever, J. A. M. A. 240:1499, 1978. Maxey, E. E.: Some observations on the so-called spotted fever of Idaho, Medical Sentinel 7:433, 1899. McCullough, G. T.: Spotted fever, Medical Sentinel 10:225, 1902. Wolbach, S. B.: Studies on Rocky Mountain spotted fever. J. Med. Res. 41 :l, 1919. Peterson, J. C., Overall, J. C., and Shapiro, J. L.: Rickettsial diseases of childhood. A clinical natholosic study of tick typhus “Rocky Mountain spotted fevei,” and murine typhus “endemic typhus,” J. Pediatr. 30:495, 1947. Harrell, G. T.: Rocky Mountain spotted fever, Medicine 28:333, 1949. Stoenner, H. G., Lackman, D. B., and Bell, E. J.: Factors affecting the growth of rickettsias of the spotted fever group in fertile hens’ eggs, J. Infect. Dis. 110:121, 1962.
905
14.
Wolbach, S. B., Todd, J. L., and Palfrey, F. W.: Pathology of typhus in man, in The Etiology and Pathology of Typhus. Being the Main Report of the Typhus Research Commission of the League of Red Cross Societies of Poland, Cambridge, 1922, Harvard University Press, pp.
28.
29.
152-256. 15.
16. 17.
18.
19. 20.
21. 22.
23.
24.
25.
26.
27.
Harrell, G. T., Venning, W., and Wolff, W. A.: The treatment of Rocky Mountain spotted fever with particular reference to intravenous fluids, J. A. M. A. 1 X:929, 1944. Woodward, T. E., and Bland, E. F.: ClinicaP observations in typhus fever, J. A. M. A. 126:287, 1944. Harrell, G., and Aikawa, J.: Pathogenesis of circulatory failure in Rocky Mountain spotted fever, Arch. Intern. Med. 83:331, 1949. Wolbach, S. B.: The pathology of the Rickettsial diseases of man, in Moulton, F. R., ed., Rickettsial Diseases of Man, Washington, 1948, American Association for the Advancement of Science, pp. 118-125. Lillie, R. D.: The pathology of Rocky Mountain spotted fever, Natl. Inst. Health Bull. 177:i, 1941. Walker. D. H.. and Mattern. W. 14.: Acute renal failure in Rocky ’ Mountain spotted’ fever, Arch. Intern. Med. 139443, 1979. Parker, R. R.: Rocky Mountain spotted fever, J. A. M. A. 110:1185, 1938. Moon, J. II., and Silverberg, S. G.: Febrile exanthem in 14-year-old boy with subseqnent development of coagulopathy, Va. Med. Monthly 98:271, 1971. Allen, A. C., and Spitz, S.: A comparative study of the pathology of scrub typhus (tsutsugamushi disease) and other rickettsial disease. Am. J. Pathol. 21:603. 1945. de Brito, T., Tiriba, A., Godoy, C. V. F., Penna, D. O., and Jordbo, F. M.: Glomerular response in human and experimental rickettsial disease (Rocky Mountain spotted fever group). A light and electron microscopy study, Path. Microbial. (Basel) 31:365, 1968. Bradford, W. D., Croker, B. P., and Tisher, C. C.: Kidney lesions in Rocky Mountain spotted fever: a light, immunofluorescence, and electron-microscopic study, Am. J. Patbol. 97:381, 1979. Levine, H. D.: Pathologic study of thirty-one cases of scrub typhus fever with especial reference to the cardiovascular system, AM. HEART J. 31:314, 1946. Gutman, A., Taragan, R., Bernheim, J., et al.: Acute renal failure in spotted fever, Harafuah 89:298, 1975.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
Wilson, L. B., and Chowning, W. M.: Studies in Pyroplasl mosis hominis (“spotted fever” or “tick fever” of the Rocky Mountains), J. Infect. Dis. 1:31, 1904. Settle, E. B., Pinkerton, II., and Corbett, A. J.: A pathologic study of tsutsugamushi disease (scrub typhus) with notes on clinicopathologic correlation, J. Lab. Ch. Med. 30:639, 1945. Bradford, W. D., and Hackel, D. B.: Myocardial involvement in Rocky Mountain spotted fever, Arch. Pathol. Lab. Med. 102:357, 1978. Pincoffs, M. C., and Shaw, C. C.: The eastern type of Rocky Mountain spotted fever. Report of a case with demonstration of rickettsiae, Med. Clin. North Am. l&1097, 1933. Walker, D. PI., Paletta, C. E., and Cain, B. 6.: Pathogenesis of myocarditis in Rocky Mountain spotted fever, Arch. Pathol. Lab. Med. 104:171, 1980. Walker, D. H., Crawford, C. G., and Cain, B. 6.: Rickettsial infection of the pulmonary microcirculation, the basis of interstitial pneumonitis of Rocky Mountain spotted fever, Human Pathology 11:263, 1980. Donohue, J. F.: Lower respiratory tract involvement in Rocky Mountain spotted fever, Arch. Xntern. Med. 140:223, 1980. Walker, D. H., Cain, B. G., and Clmstead, P. M.: Laboratory diagnosis of Rocky Mountain spotted fever by immunofluorescent demonstration of Rickettsia rickettsii in cutaneous lesions, Am. J. Clin. Pathol. 69:619, 1978. Woodward, T. E., Pedersen, C. E., Jr., Oster, C. N.; Bagley, L. R., Romberger, J. and Snyder, M. J.: Prompt confirmation of Rocky Mountain spotted fever. Identification of rickettsiae in skin tissues, J. Infect. Dis. -l34:297, 1976. Fein, A., Grossman, R. F., Jones, J. G., Overland, E., Pitts, L., Murray, 9. F., and Staub, N. C.: The value of edema fluid protein measurement in patients with pulmonary edema, Am. J. Med. 67:32, 1979. Shoemaker. W. C.. and Hauser. 6. J.: Critiaue of crvstalloid versus’ colloid therapy in sllock and shock “lung, Critical Care Med. 7:117, 1979. Stein, L., Beraud, J., Morissette, M., daLuz, P., Weil, M. H., and Shubin, H.: Pulmonary edema during volume infusion, Circulation 52:483, 1975.
December,
1980,
Vol.
100,
No.
6, part
I