Advance Pathology Services, P.C Professional Drive, Suite 3 Cadillac, MI Phone: Fax:

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1 Advance Pathology Services, P.C Professional Drive, Suite 3 Cadillac, MI Phone: Fax: Pathology Analysis: Pneumonia and Pulmonary Hemorrhage Cause Death; Clinically Developed ARDS Involved 1 P a g e ARH System APRIL 2, 2010: This 20 y.o. white female presented to the emergency department of the ARH System with a chief complaint of a persistent productive cough for the past month. The patient was producing a small amount of mucus with blood streaks present. She reported that the symptoms had a gradual onset. On review of systems, no chest pain or shortness of breath was reported at this time. The patient had a positive 3 pack year history of smoking. The remainder of the review was unremarkable. The physical exam showed an obese white 20 y.o white female with no significant abnormalities. The patient s vital signs were reported as T = 97.9 o, BP = 170/95, P = 100 and R =16. The patient s O 2 saturation was 98% on room air. Laboratory tests showed minimal abnormalities. A complete blood count demonstrated an absolute neutrophilia [9.4 K/ml )]. The patient s hemoglobin (Hgb), platelet count, aptt and PT were within the reference ranges. A chest X-ray (CXR) was unremarkable. A diagnosis of hemoptysis secondary to bronchitis was made by the physician. The patient was placed on azithromycin (250mg po qd) for five days. She was also advised to stop smoking. APRIL 9, 2010: The patient again presented to the ARH System emergency department at 10:36. At this time her symptoms had progressively worsened. She reported continued hemoptysis with shortness of breath exasperated by exertion, sinus congestion and a sore throat. The physical exam showed decreased breath sounds and ronchi present. The patient was tachypneic with R = 22. The patient s O 2 saturation was 887% on room air. The patient s other vital signs were P = 102, BP = 145/78 and T= 98.4 o. Laboratory tests show a continued absolute neutrophilia (13.9 K/ml) and the development of an absolute monocytosis. There is also an elevation of the platelet population to 440K/ml. The tests also show an increased ESR [41mm/hr (<20)] and C-reactive protein [CRP; 5.1mg/dl (<1.0)].These changes are consistent with a reactive process such as infection.

2 The patient s Hgb dropped 0.7g to 11.9g/dL from that reported on April 2 nd. This indicating a possible blood loss verses hydration status change. The D-dimer was elevated to258 ng/ml (<230). D-dimer is a break down product from blood clots. It can be seen in reactive processes, thrombosis and Disseminated Intravascular Coagulation (DIC). The patient was placed on low molecular weight heparin sq. Urine analysis showed a trace amount of blood and leukocyte esterase. Microscopic examination of the urine showed rare RBCs and WBC/hpf. Urine C&S results at that time showed no evidence of a UTI. The patient was admitted to the hospital at this time. Treatment with azithromycin was continued via IV. Rocephin [cefttriaone (1gm/d IV)] was added to the antibiotic regiment. She was placed on O 2 which was titrated to an O 2 saturation of >90%. A sputum Gram stain and sputum cultures and sensitivities were ordered at 7pm. No blood cultures were ordered. No microbiology results are noted in the record for these tests. A CXR at this time demonstrated mild bilateral interstitial infiltrates. These were noted mainly in the mid and lower lobes of the lungs. This was followed up by a CT of the chest with contrast. The CT was limited in visualizing the vasculature due to distribution of the contrast media. No evidence of a pulmonary embolism was noted. Multiple reticular-nodular opacities were noted centrally in the right upper lobe posterior segment. There was mild hilar lymphadenopathy noted. The radiologist gave an abbreviated differential diagnosis including pneumonia, TB and neoplasm. April 10: Progress notes indicate that the patient was feeling better. No hemoptysis was reported in the am. There was still a slight cough and she remained short of breath of O 2. The CBC shows resolving of the neutrophilia and monocytosis at this time. The patient Hgb shows a drop of 1.5g/dl suggesting the possibility of hemorrhage vs rehydration. The CRP has decrease to 4.2mg/dl at this time. This suggests resolving inflammation. April 11: Progress note indicates that Patient had tachycardia (p=136) and a decreased O 2 saturation (71%) while ambulating in the hallway on room air at 6:00am. By 12:45pm the doctor reports that there has not been anymore hemoptysis and there is no sputum production. The lung fields have bilateral 2 P a g e

3 rales present. At 3:45 the note indicates plans for a bronchoscopy to investigate the reticular nodular infiltrate seen on CXR in hrs. The CBC at this time shows the development of an absolute eosinophilia (700/ml). Her Hgb and WBC are stable. There is a slight thrombocytosis reported. April 12: At 12:45 the physician s progress note shows a generally improving patient. A second note at 13:33 again shows no indication of distress in the patient. At this point the progress notes stop. The following information comes from the physician s orders and nursing notes: 15:26: VQ scan for PE was ordered. This showed no evidence of a pulmonary embolism. 15:30: Patient is transferred to ICU. In the discharge summary, dictated by Dr. H on 4/26/11, she notes that the patient was transferred to ICU for hypoxia. Doppler studies of the legs, d-dimer and troponin are ordered at this time. The D-dimer was elevated at 467ng/ml. The troponin-i level was within the reference range. The Doppler studies showed no evidence of deep venous thrombosis. 16:00: the patient was placed on Sol-Medrol and plans were made for a bronchoscopy in the morning. 16:19 Nursing notes show the patient is short of breath and cannot lie down. Her pulse rate was in the 150s. SatO 2 = 87% on 2L/min of O 2 which was increased to 4L/min. 17:30: STAT CXR is ordered. The results showed perihilar interstitial infiltrates bilaterally. 19:35: Ativan 1mg po q 2hrs for agitation/anxiety was ordered for up to three doses. 21:00: O 2 increased to 2-6L via nasal cannula to maintain sato 2 >90%. 22:00: Patient becomes tachypneic on 4L of O 2. 23:50: O 2 was switched to an aerosol mask for the night. April 13: Patient was ordered transferred to VPMC via helicopter at 00:06. IV H block started for transfer ordered at 02:20 and patient then transferred. 3 P a g e

4 University of X Medical Center Mercy Hospital April 13: Arrived and initially accessed at ~3:45am and admitted to ICU. At this time the patient was alert and oriented x3. Vital signs showed her to be tachypneic (R = 26) and tachycardic (P =117). Her blood pressure was within normal limits (BP = 113/51). The lung fields are clear and equal. The physical exam was otherwise unremarkable. O 2 increased to 10L/min with a sato 2 = 89-94%. Medications were continued as before with the addition of prednisone 60mg po qd for possible eosinophilic PNA. Cultures for acid fast bacteria were ordered. Testing for influenza RNA and Legionella urinary antigen was ordered. Plans for an open lung biopsy by thoracic surgery were made by Dr. Gilbert. During the course of the day the Patient s respiratory status deteriorated. At this point she was intubated. There was significant blood bilaterally from the airways on intubation. The doctor performing the intubation thought that the blood might be greater coming from the right broncus. Suctioning of the airways produced thin bloody material but no clots. Clinically the patient was presenting with ARDS. At this point she was placed on PEEP with 100% O 2. Continued efforts to increase her oxygenation were unsuccessful. The patient s Hgb dropped to 6.4g/dl indicating a substantial hemorrhage. It was suspected that this was a pulmonary hemorrhage by the intensivist. Patient continued to decompensate and arrested. After 45min of ACLS, efforts were stopped and she was pronounced. Ante mortem sputum and BAL cultures were obtained on April 13 th. Examination of the sputum showed no significant changes. The culture from the left lung grew alpha hemolytic Streptococci and yeast consistent with Candida albicans on April 15th. Other cultures were negative. Autopsy Results Review of the gross autopsy findings show abnormalities bilaterally in the lungs. Both are nearly twice as heavy as normal: left lung = 940g ( ) and right lung = 1048g ( g). On sectioning, both are congested and express bloody fluid. Numerous small nodular lesions are noted. The remaining findings in the autopsy are noncontributory. No microscopic descriptions of the tissues are provided in the autopsy report. Instead a statement that the microscopic findings support the reported diagnoses is present. The primary diagnosis reported for the lungs is bilateral diffuse severe bilateral acute and organizing bronchiolitis and pneumonia with associated lung injury and hemorrhage. This is diagnostic of diffuse alveolar damage as reported in the cause of death. 4 P a g e

5 Postmortem blood cultures reported positive growth for coagulase negative Staphylococcus and anaerobic Preoionibacterium species. Unfortunately, the time for isolation and quantitative results are not documented. This makes it difficult to determine if the coagulase negative staphylococcus is a contaminate or pathogen. Most likely it is a contaminate. The acid fast culture of the tissue showed Gram positive cocci present. These are not further identified. The remaining autopsy cultures were negative for growth. Observations As a general rule before antibiotic treatments are started, bacterial cultures and sensitivities should be drawn. This allows for the identification of the bacteria causing the infection and the identification of the antibiotics that will be most effective in the treatment of the infection. In Patient s case I found an order for the appropriate cultures to be drawn but no reported results from ARH System. Results of cultures done at UPMC only became available after Patient s death. The bronchial culture was positive for coagulase negative Staphylococcus. Coagulase negative Staphylococcus is a common skin bacterium. It is often isolated in clinical specimens. This organism can be either a pathogen or contaminant. Because of this it is important to know the amount of organisms isolate and how fast they grew in culture. Bacteria that are causing an infection usually are noted in the first 24 hours and in large numbers. Contaminants usually are present in low numbers as isolated colonies and tend to take longer to appear. Unfortunately this information is not given in the laboratory report. Coagulase negative Staphylococcus also tends to be a very antibiotic resistant organism. Because of this it is necessary to get antibiotic sensitivities to select the right antibiotic for therapy. Often the infection must be treated with the antibiotic Vancomycin. Ceftriaxone is a third generation cephalosporin antibiotic with a broad spectrum of coverage. It is often used for treatment of community acquired infections such as bronchitis. The drug is related to penicillin and people that are allergic to penicillin sometimes will also have a reaction to ceftriaxone. The drug is widely used and is generally safe. In reviewing the on-line literature, it is known that about 6% of patients treated with ceftriaxone will develop a peripheral eosinophilia. Eosinophilic pneumonia has been reported in 0.12% of patients with side effects treated with ceftriaxone. All these cases developed in less than 1 month of the start of treatment and 2/3 of the cases were in year olds. Ceftriaxone has also been associated with prolonged prothrombin times. 5 P a g e

6 Eosinophils are a class of white blood cells. They are associated with parasitic infections, allergic and drug reactions. When they are increase in the circulating blood this is known as eosinophillia. They can collect in tissues in response to infections or chemicals. When this happens in the lungs it is referred to as eosinophilic pneumonia. Conclusion In my opinion, Patient died of eosinophilic pneumonia and pulmonary hemorrhage secondary to an idiosyncratic (rare) reaction to ceftriaxone (Rocephine). Patient developed an eosinophillia approximately 48 hours after the IV ceftriaxone was started. Shortly thereafter she clinically developed Adult Respiratory Distress Syndrome. Clinically an eosinophilic pneumonia was suspected. This is supported by the autopsy finding of diffuse alveolar damage in the lungs. As noted above ceftriaxone has been associated with both eosinophillia and eosinophilic pneumonia. There was also an elevation in Patient s serum D-dimer levels. This can be seen with pulmonary emboli and vascular thrombi, both of which were ruled out by clinical testing. It can also be elevated with ineffective coagulation, such as in disseminated intravascular coagulation. Disseminated intravascular coagulation occurs when the body is stressed, such as in sepsis or shock. The blood clotting system is activated throughout the body but does not form clots. Instead the blood loses its ability to prevent bleeding. The patient tends to ooze blood through minor traumas. This would be consistent with the hemorrhages developing in Patient s lungs. Ceftriaxone has also been associated with prolonged prothrombin times. This may have contributed to the hemorrhage in the lungs. 6 P a g e