3Learning ObjectiveTo present a case of Severe Leptospirosis and discuss its diagnosis, pathogenesis, complications and mode of treatment.
4Identifying Data D.D. 25 year old female Filipino single Chief Complaint: Fever
5History of Present Illness 4 days PTA- undocumented intermittent fever (+) body malaise, (+) dry cough (+) sorethroat, (-) colds, rashesself-medicated with paracetamol affording temporary relief.
6History of Present Illness Few hrs PTA - persistence of symptoms (+) diarrhea, 2x (+) crampy epigastric pain (+) nausea(-) vomitingAdmission(loose, watery, yellowish, non mucoid, non bloody stool. Patient went to the ER and was subsequently admitted.
7Review of systems (-) headache (-) dizziness (-) difficulty of breathing(-) orthopnea(-) paroxysmal nocturnal dyspnea(-) palpitations(-) dysuria(-) urinary frequency(-) joint painsReview of systems was unremarkable
8Past Medical History Diagnosed w/ Leptospirosis 7 yrs ago Unrecalled work upAdmitted St Paul’s Hospital for several daysGiven unrecalled IV antiboticsNon hypertensiveNon diabeticNon asthmaticNo known allergiesNo previous operationDuring that time, patient presented with fever, myalgia and headache. Several unrecalled labs were done and was apparently positive to Leptospirosis. Patient was given unrecalled IV antibiotics and was discharged after several days.
9Family History (+) Hypertension- father (+) DM- mother (-) Bronchial asthma(-) PTB(-) Cancer
10Personal/ Social History Non smokerNon alcoholic beverage drinkerWorks in the officeWorks in the office as a filing clerk and lives in a condo in Makati City wit her brothers.
11Physical ExaminationGeneral survey: conscious, coherent not in respiratory distressVital signs: BP 110/70, HR: 98 RR: 20, T: 38cSkin: No rashes, no jaundiceHEENT: pinkish palpebral conjunctivae, anicteric sclerae, no nasoaural discharge, no tonsillopharyngeal congestion, dry lips and tongue, no cervical lymphadenopathy, flat neck veinsPatient’s physical examination was essentially unremarkable except for fever, dry lips and tongue and flat neck veins
12Physical ExaminationChest/Lungs: equal chest expansion, no retraction, clear breath soundsHeart: Adynamic precordium, normal rate, regular rhythym, S1 louder than S2 at the apex, S2 louder than S1 at the base, PMI at 5th ICS, LMCL, no murmurAbdomen: flabby, normoactive bowel sounds, soft, no tenderness, no palpable mass, no hepatosplenomegalyExtremities: no gross deformities, no edema, no cyanosis, full and equal pulses
13Salient features 25 y.o, F, single cc: fever x 5 days body malaise, dry cough, sore throat(+) 2 episodes of diarrhea(+) crampy epigastric pain(+) nauseaP.E. Temp= 38cFlat neck veinsDry lips and tongue
14At the E.R.Blastocystis hominis –a non pathogenic yeast and is believed by some to be a protozoan capable of causing intestinal disease. Usually not treated in asymptomatic patients. Other causes of diarrhea should be sought. But if diarrhea is prominent w/ no other attributable cause, may give metronidazole or other 5 nitro-imidazole like secnidazole
16Initial ImpressionAcute gastroenteritis with some signs of dehydrationT/C Dengue fever
17Course in the Wards 1st hospital day (8/3) intermittent fever (D6) (Tmax c)bloatednesscrampy epigastric paindiarrhea, 8xvomiting, 1xSecnidazole 500mg/tab. 4 tabs as single doseMetoclopramide 10 mg Iv push q8Loperamide 2 tabs x 1 doseIVF rate: increased to 166 cc/hr.Secnidazole- is a 5-nitroimidazole which has a high antiparasitic effect against a wide variety of anaerobic protozoal parasites and bacteria. Blastocystis hominis –a non pathogenic yeast and is believed by some to be a protozoan capable of causing intestinal disease. Usually not treated in asymptomatic patients. Other causes of diarrhea should be sought. But if diarrhea is prominent w/ no other attributable cause, may give metronidazole or other 5 nitro-imidazole like secnidazole
18Course in the Wards 1st hospital day (8/3) PTT (n.v secs)PT was normalplt ct 69,000 from 109,000> Monitoring of platelet ct q 12 hrs.>Stand by 4 units of FFPPTT was elevated at There was further decrease in platelet count. There were no any signs of bleeding at this point like gumbleeding or osebleeding. Fresh frozen plasma contains stable coagulation factors and plasma proteins (fibrinogen, antithrombin, albumin, prot c&s). INDICATIONS for FFP: correction of coagulopathies, rapid reversal of warfarin, TTPPTT & PTT assess plasma coagulation function. PTT screens the intrinsic limb of the coag system and tests for the adequacy of factors VII, IX, XI, XII……. PT screens the extrinsic or tissue dependent pathway
192nd hospital day (8/4) on and off fever (D7) (37.0- 39.5 c) bloatednesscrampy epigastric pain7 episodes of LBM3 episodes of vomitingdirect epigastric tendernessPlain film of the abdomen: no localizing signshydration/meds were continuedadditional dose of Loperamide and Eldicetstarted Vamin glucose
21Course in the Wards 2nd hospital day (8/4) Lab testKBUNcreatinineK correction was given. (kcl drip: 100cc pnss+30 meqs kcl x 4 hrs for 2 doses)Accurate Input and output monitoring and rpt electrolytes were requested
22Course in the Wards 2nd hospital day (8/4) Problem: (+) Difficulty of breathingRespiratory rate: 26Flat neck veinsClear breath soundsABG: uncompensated metabolic acidosis. pO2=96.9, pH=7.28, Pco2=20.1, HCO3=9.3, O2 sat=96.8, B.E.-14.9, Total CO2=9.9, RR=26, Rm airgiven NaHCO3 IVMetabolic acidosis: can be due to 1) diarrhea (loss of bicarbonate)2) renal failure (accumulation of endogenous acids)Anion gap (nv mmol/l) formula: AG=[Na] - (Cl + hco3)-represents those unmeasured anions (anionic proteins, sulfate,and organic ions) in plasmaAn INCREASE in AG may be due to a decrease in unmeasured cations (Ca, Mg, K) or an increase in unmeasured anions
24Course in the Wards 2nd hospital day (8/4) CBC: Hgb 8.2, hct 23.6, seg 8,320, seg 77, lym 17 and plt ct 71,000>Reserved 2 u prbc>repeat CBC w/ plt ct in am>Blood culture done>Referred to Nephrology & Infectious disease serviceNoted to have anemia with a hgb 8.2 from PLt ct 71,000 fro 64,000.
253rd hospital day (8/5) (+) fever (D8) (Tmax39.6 c) (+) Epigastric tenderness(+) decreased BM (semi-formed to soft)(-) vomitingRpt CBC: Hgb 8.4, hct 24.4, plt ct 84,000 from71,000Transfused 1 of 2 unit PrbcIncreased omeprazole to 1 cap BID
26Course in the Wards 3rd hospital day (8/5) PTTPT: Activity 66.4% INR 1.2Vitamin K givenUrinalysis showed proteinuria +2, Blood +3, elev RBC 572.2, elev WBC 14.4Urine CS requested
273rd hospital day Problem: (+) dyspnea (+) distended neck veins (+) bibasal crackles(+) bipedal edemaLasix 40mg IV givenIVF rate was decreased to 40cc/hrCentral line inserted (13-14 cmH2O)
293rd hospital day (8/5)Stat ABG: Po , Ph 7.27, Pco , HCO , O2 sat 83,B.E.-10.9, TCO2 15.7, RR 28 (O2 2LPM via Nasal cannula).> Nasal cannula was shifted to MVM> stand by intubation> scheduled for stat Hemodialysis
30Course in the Wards 3rd hospital day (8/5) Spec (pre HD)K 2.7, Ca 1.5, total protein and Albumin 1.6bun 23, crea 3.1, SGOT 336, SGPT 78 and T. Bili 1.4.Given K, Ca, and albumin correction
31Course in the Wards 3rd hospital day (8/5) During dialysis: transfused w/ 4 units FFP (150cc/unit/bag)=600cc1 unit Prbc (250cc)550cc flushing/ medsNa HCO3 40 cc/hr x 4 hrs= 160ccCa Gluconate 80 cc/hr x 4 hrs= 320ccKcl drip 10% 40meqs x 4 hrs = 100ccUF Volume (output)=4,000 ccHD total Input= 1,980 cc
38ABG 1 hr post intubation still showed hypoxemia (pO2 58, O2 sat 91 Atrovent neb givenPEEP was increased to 7.5Patient immediately underwent (2nd)hemodialysis
39Course in the Wards 4th hospital day (8/6) Pre HD Labsdecreased serum K (2.4 from 2.7), Ca 1.9, Phosphorus 2.3 and Mg 1.6 ( ).Serum creatinine further increased (4.6 from 3.1)Patient was given K, Ca, Mg and phosphorus correction
40Course in the Wards 4th hospital day (8/6) During dialysis:100cc flushing/ medsPNSS 40 cc/hr x 4 hrs= 160ccVamin glucose 40 cc/hr x 4 hrs= 160ccAlbumin 50ccHD total Input= 470 ccUF Volume (output)=3,000 cc
41Course in the Wards 5th hospital day (8/7) afebrile(+) tachycardia ( )(+) decreased urine output (4-5cc/hr)JVP 13cmH2OLasix was continued
43Course in the Wards 5th hospital day (8/7) Patient underwent 3rd hemodialysis.During dialysis:50cc flushing/ medsK Phos 40mmol in PNSS 100ccx 4hrs= 100ccCa Gluc 5 g in 450cc pnss x 20cc/hr x 4=80ccMgSO4 5 g in 500cc PNSS X 20cc/hr x 4=80cctotal Input= 470 ccUF Volume (output)=2,000 cc
44Course in the Wards 5th hospital day (8/7) Pulmonary service was able to bring down FiO2 to 0.6 but had desaturationeventually placed back to 100% FiO2More bloody secretions coming out/ suctioned from ETFrequent/ prn suctioning of secretions.PEEP was increased to 10.
45Course in the Wards 5th hospital day (8/7) CBC: Hgb 12.1, hct 35.1, wbc (15, 760 from 6,850), seg 74, plt ct 135,000 fro 128,000).Pen G was discontinuedPiperacillin Tazobactam 2.25 IV q8 was started.Total Input: 2,298ccTotal Output: 2,107cc(Urine 107 cc+ HD 2,000cc)
46Course in the Wards 6th hospital day (8/8) afebrile (D2)lesser bloody secretions from ET.Persistent oliguria (4-5 cc/hr)Lasix was continuedpatient had another dialysis (4th)
47Course in the Wards 6th hospital day (8/8) During dialysis:50cc flushing100cc OFCa Gluc 5 g in 450cc pnss x 20cc/hr x 4=80ccDialysis terminated due to BP 94/63 (3rd hr)Bp went up 110/70 aftertotal Input= 230 ccUF Volume (output)=1,700 cc
48Course in the Wards 6th hospital day (8/8) chest xray post HD: clearing of bilateral lung infiltrates.FiO2 was titrated down to 30%.
50Course in the Wards 6th hospital day (8/8) Problem: desaturation (02 sat 50%).Fi0 was increased to 100%suctioning of secretionsambubaggingBP noted to be 0, HR 0.hooked to a cardiac monitor: flat line.CPR doneGiven epinephrine 1 dose
51Course in the Wards 6th hospital day (8/8) revived after 3 minutesDopamine drip was started.Bp went up to 110/70 from 50 pallpatoryABG: mixed (slight) metabolic and respiratory acidosis with PO2 496 at FiO2 1.Patient became fully awake and responsive
52Course in the Wards 6th hospital day (8/8) 30 mins after referred again (O2 desaturation 80%)suctioned secretionsBP=0, HR=0, flat line on cardiac monitorCPR was done but after 15 minutes, relatives ordered to discontinue CPRPatient was then declared expired.
57Problem #1 Persistent fever Malaria Points for>Fever spikesPoints AgainstNo history of travel to endemic areasProminent diarrhea and abdominal pain suggests another dx>non specific symptoms (no headache, chills)
69Problem # 3 Difficulty of Breathing P> Nasal cannula was shifted to MVM> stand by intubation--Intubated> Hemodialysis> NaHCO3 IV> CVP monitoring> Accurate I & O
70Problem# 4 Hypokalemia S> (+) diarrhea x several episodes (+) vomiting x several episodesA> Hypokalemia probably 2 to GI loss (diarrhea)P> Na, k, crea monitoringKCL dripurinary K excretion- not done
71Problem #5 ANEMIA S> (+) bloody/frothy secretions suctioned per ET (-) black stools/ bloody stoolsO> pale palpebral conjunctivae(-) Petechiae(-) bruises
72Hgb Hct RBC WBC Seg Lym Mon Plt ct DOA 1st HD 2ndHD 3rdHD AM 3RDHD PM 5THHD6THHDHgb22.214.171.124.414.810.4Hct35.530.823.624.442.335.130.2RBC126.96.36.1995.34.4WBC13,4707,9608,3206,85015,65015,76016,580Seg91807779767475Lym618171514Mon24910Plt ct109,00069,00071,00084,000128,000135,000180,000
73Problem #5 ANEMIA A> Anemia probably secondary to acute blood loss (T/C Alveolar /Interstitial hemmorhage)T/C Anemia secondary to renal failureT/C Anemia secondary to SepsisP> CBC monitoringBlood transfusion(2 u prbc)PT/PTT- prolonged PTT (49.6)Peripheral smear:rbc: normocytic, normochromic,pletelets: decreasedPERIPHERAL SMEAR: can provide important information as to the presence and nature of erythropoeitic defectReticulocyte count (nv 1-2): percent of newborn rbcs in the circulating red cell population. Elevated retic ct provide a reliable measure of rbc production in response to anemia.CBC and reticulocyte index are used to intially classify an anemia as either hypoproloferative (a maturation disorder) if (<2) or hemolytic/ hemorrhagic anemia If (>3).
74DIAGNOSIS #1 Severe Sepsis (Leptosprosis) #2 Acute renal failure probably Intrinsic and pre renal secondary to leptospirosis and dehydration (GI fluid loss)#3 Acute respiratory failure 2 to #2#4 Anemia probably secondary to alveolar hemorrhage, renal failure and Sepsis#5 Hypokalemia secondary to GI loss (diarrhea)Severe sepsis: sepsis with 1 or more signs of organ dysfunction, hypoperfusion or hypotension, such a metabolic acidosis,oliguria/anuria
75Cause of Death ? Mucus Plug Septic Shock Arrhythmia Hypokalemia Pulmonary Embolism
76Cause of Death ? Points For Points Against Mucus plug Sudden dyspnea Sudden O2 desaturation(+) mucus plugs/ big blood clots on the tip and inside the lumen of the Endotracheal tube upon removalSeptic ShockElevated WBC count16,580 from as low as 6,850Tachycardia(+) Leptospira IgMHad O2 desaturation first before BP went downSeptic shock: sepsis with hypotension that is unresponsive to fluid resuscitation plus organ dysfunctionSevere sepsis: sepsis with 1 or more signs of organ dysfunction, hypoperfusion or hypotension, such a metabolic acidosis,oliguria/anuria
77Cause of Death ? Points For Points Against Arryhthmia/ Hypokalemia Cardiac monitor: showed no arrythmiaImproving K level (2.9 from 2.4) w/ ongoing correctionPulmonary EmbolismSudden onset dyspnea, O2 desaturation, tachycardia,Patient is relatively immobile (intubated)pO2 400
79Leptospirosis zoonosis with protean manifestations caused by the spirochete, Leptospira interrogans
80Infection in small rodents (carrier animals) usually occurs during infancy animals shed the organism in their urine intermittently or continuously throughout life resulting in contamination of the environment, particularly water.Organisms may remain viable for days to months in soil and water with a neutral pH.
81Portals of entry include cuts or abraded skin, mucous membranes or conjunctiva. The infection is rarely acquired by ingestion of food contaminated with urine or via aerosols.Controversy exists as to whether Leptospira can penetrate the intact skin.
82Risk factors for infection Occupational exposure — farmers, ranchers, abattoir workers, trappers, veterinarians, loggers, sewer workers, rice field workers, military personnel, laboratory workersRecreational activities — fresh water swimming, canoeing, kayaking, trail biking
83Household exposure — pet dogs, domesticated livestock, rainwater catchment systems, and infestation by infected rodents.Other — Skin lesions, contact with wild rodents
84The spirochetes enter the host through abraded skin or intact mucous membranes and travel to the liver where they reproduce.After an incubation period of 2 to 30 days (usually 5 to 14 days), leptospiremia occurs, spreading organisms to all parts of the body including the meninges
85LEPTOSPIROSIS 2 general patterns occur: 1 anicteric leptospirosis (90%)2 icteric leptospirosis or Weil disease (10%)
86CLINICAL MANIFESTATIONS fever (75 to 100)Myalgias (50-80%)headache (15-30%)nonproductive cough (25 to 35%)nausea, vomiting and diarrhea (50%)
87less common symptoms:arthralgiasbone painsore throatabdominal pain
88Physical examinationconjunctival suffusion- (40-70%)muscle tenderness (30-40%)Jaundice (50-80% in severe form)SplenomegalyLymphadenopathyPharyngitisHepatomegalyskin rash
89Liver failure is generally reversible and not a cause of death in leptospirosis. Dyspnea, oliguria, WBC counts above 12,900/mm3Alveolar infiltrates on chest radiography have been associated with adverse outcomes.
90Complications — While most cases of leptospirosis are mild to moderate, the course may be complicated by renal failure, uveitis, hemorrhage, acute respiratory distress syndrome, myocarditis and rhabdomyolysis
91The potential severity of leptospirosis was illustrated in a retrospective study of 60 patients with leptospirosis requiring ICU admission in India .Multiorgan failure developed in 46 patients (77 percent)the mortality for patients with leptospirosis requiring ICU admission was 52 percent.
92Severe pulmonary disease may be underdiagnosed in regions of high endemicity. Among 321 patients with serologic and clinical evidence of leptospirosis in Peru, seven (3.7 percent) had severe pulmonary manifestations, including hemoptysis in six5 of the 7 patients died, 4 from pulmonary hemorrhage and 1 from acute respiratory distress syndrome and multiorgan failure
93LABORATORY FINDINGS — Leptospirosis is a nonspecific clinical illness, and routine laboratory tests are similarly nondiagnostic.White blood cell (WBC) counts are generally less than 10,000/mm3 but may range between 3,000 and 26,000/µLUrinalysis frequently shows proteinuria, pyuria, granular casts and occasionally microscopic hematuriaElevated creatine kinase is found in approximately 50 percent of patients and may be a useful clue for the diagnosis
94Approximately 40 percent of patients have minimal to moderate elevations of hepatic transaminases (usually <200 IU/L). Hyponatremia is common in severe leptospirosis.
95Thrombocytopenia is uncommon, but a poorly understood hemorrhagic diathesis may occur in the absence of demonstrable coagulation defects or severe thrombocytopenia. Pancytopenia has been reported as the presenting manifestation in case reports with complete resolution following treatment with penicillin . The CSF may show a neutrophilic or lymphocytic pleocytosis with minimal to moderately elevated protein concentrations and normal glucose. A low CSF glucose concentration is rarely seen .
96Imaging — Chest radiographs may show small nodular densities, which can progress to confluent consolidation or a ground glass appearance Pathologically, these infiltrates may represent alveolar hemorrhage, ARDS, or pulmonary edema
97DIAGNOSIS — Because the clinical features and routine laboratory findings of leptospirosis are not specific, a high index of suspicion must be maintained for the diagnosis. The organism can be cultured, but the diagnosis is more frequently made by serologic testing.
98Culture — As noted above, leptospirosis can be confirmed by culture of the organism from clinical specimens in appropriate media. BBlood and CSF specimens are positive during the first 10 days of the illness. IIsolation of the organism from the blood is successful in approximately 50 percent of cases.Urine cultures become positive during the second week of the illness and remain so for up to 30 days after the resolution of symptoms
99Serology — Because some clinical microbiology laboratories do not offer culture for the diagnosis of leptospirosis, serological tests are most often used for confirmation.A number of serologic tests are employed or are under development, including the microscopic agglutination test (MAT), macroscopic agglutination test, indirect hemagglutination, and ELISA
100While all of these assays are useful in establishing the diagnosis, the gold standard is considered to be the MAT Unfortunately, this test requires live organisms, considerable expertise, and is performed only by reference laboratories such as the CDC.Like other serologic tests, the MAT is most specific when a fourfold or greater rise in titer is detected between acute and convalescent serum specimens. However, a single titer of >1:800 is strong evidence of current or recent infection with leptospira.
101Cross reactive antibodies have been associated with syphilis, relapsing fever, Lyme disease, and legionellosis . The level of the antibody titers as found in the MAT cannot be used to predict the serovar that infects the individual patient
102Since the MAT is not readily available, another assay typically is performed first in suspected cases of leptospirosis.Two commercially available rapid tests, the microplate IgM ELISA and an IgM dot-ELISA dipstick test, performed well in studies conducted in the United States and Thailand that used MAT as the comparatorIf one of these assays is positive, sera for MAT can then be sent to the CDC
103LEPTOCHECK (Rapid test for antibodies to Leptospira) Sensitivity 100% (only 90% in a study made in India by Maskey et at)Specificity 92% (Maskey et at)
104TREATMENT — The vast majority of infections with leptospira are self-limiting. Although penicillins, tetracyclines, chloramphenicol, and erythromycin have anti leptospiral activity in vitro and in animal models, it remains controversial whether antimicrobials produce a beneficial effect in mild human leptospirosis since the illness has a variable natural history.
105Nevertheless, if the illness is severe enough to result in a physician visit and the diagnosis is recognized, antibiotic therapy should be given.
106Efficacy — Two small, randomized, placebo-controlled trials have shown a benefit from antimicrobial therapy. In one in which doxycycline (100 mg PO twice daily) was compared to placebo, doxycycline shortened the illness by an average of two days and prevented shedding of the organism in the urine .
107In the second trial, patients with severe leptospirosis who were treated with penicillin (6 million units daily) had fewer days of fever, more rapid resolution of serum creatinine elevations, and a shorter hospital stay; penicillin therapy also prevented urinary shedding
108Supportive care with dialysis, ventilatory support, and blood products may be necessary in severe cases of leptospirosis.Antimicrobial treatment — Human leptospirosis is often self-limited and requires no antibiotic treatment.Symptomatic patients presenting for medical care should be treated to shorten the illness and decrease shedding of the organism in the urine. We suggest the following approach that varies with the clinical presentation
109We suggest treatment with oral doxycycline for outpatients because it is also effective for rickettsial disease, which can be confused with leptospirosis (100 mg orally twice daily in adults; 2 mg/kg per day in two equally divided doses in children 8 years of age to a maximum dose of 200 mg daily).
110The exceptions are children 8 years or pregnant women, in whom we suggest treatment with amoxicillin (25 to 50 mg/kg in three equally divided doses).
111For hospitalized adults with severe disease, we suggest intravenous therapy with penicillin (6 million units daily), doxycycline (100 mg twice daily), ceftriaxone (1 g every 24 hours), or cefotaxime (1 g every six hours).
112PROGNOSIS — Mortality rates in hospitalized patients with leptospirosis have ranged from 4 to 50 percent.Pulmonary hemorrhage (30-70%) A retrospective review of 282 cases of leptospirosis during a 2002 outbreak in India identified risk factors for mortality
113Most authorities agree that if antibiotics are not started early in the disease (up to the fourth day), they do not change the course of the illness (50-80%motality)
114PREVENTION — Vaccination of domestic animals against leptospirosis provides substantial protection, but is not effective in 100 percent of animals. Some immunized animals become infected and excrete leptospires in their urine.
115The major control measure available for humans is to avoid potential sources of infection such as stagnant water, water derived from run off from animal farms, rodent control, and protection of food from animal contamination.